Pyrazol-1-yl phenoxyacetic acid compounds which have useful pharmaceutical utility

ABSTRACT

We proposed a novel compound having an activity of PGI 2  receptor agonist. 
     A phenoxyacetic acid derivative of the formula ##STR1## A is --C(R 1 )═N˜OR 2 , --CH(R)NH--OR 2 , --COE, --SO 2  E, --CH 2  --NR 3  --Y, --Z -- NR 3  --CONR 4  R 5 , --CH 2  --OR 6 , --CO 2  R 6 , --CH 2  --O˜N═CR 7  R 8 , --CH 2  --O--NHCHR 7  R 8 , substituted by imidazolyl(methyl), pyrazolylmethyl, oxazolyl(methyl), thioxazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolylmethyl; 
     T is alkylene, alkenylene, etc.; 
     D is --CO 2  R 10 , --CONR 11  R 12  ; 
     E is (substitution) amino, hydradino; 
     Y is substituted (thio) carbonyl, substituted sulfonyl; 
     Z is --CH═N--, --CH 2  NR 3  --; 
     R 1 , R 3 , R 10  -R 13  is each H or alkyl, etc.; 
     R 2 , R 4  -R 9  is each H, alkyl or alkyl substituted by phenyl or hetero ring, etc. and non-toxic salts thereof, non-toxic acid addition salts thereof, possess an agonistic on PGI 2  receptor, so it is useful for prevention and/or treatment of thrombosis, arteriosclosis, ischemic heart diseases, gastric ulcer and hypertention.

DESCRIPTION Phenoxyacetic acid derivatives SUMMARY

This invention is related to phenoxyacetic acid derivatives.

More particularly, this invention is related to:

1) phenoxyacetic acid derivatives of the formula (I): ##STR2## whereinall the symbols are the same meaning as hereafter defined, and non-toxicsalts thereof and non-toxic acid addition salts thereof,

2) processes for the preparation thereof, and

3) pharmaceutical agents containing them as active ingredient.

BACKGROUND OF THE INVENTION

Prostaglandin I₂ (PGI₂)is a physiologically active natural substancehaving the following structural formula, which is biosynthesized fromProstaglandin H₂ (PGH₂) in the metabolic process the called arachidonatecascade. ##STR3## (see Nature, 263, 663(1976), Prostaglandins, 12,685(1976), ibid, 12, 915(1976), ibid, 13, 375(1977) and Chemical andEngineering News, Dec. 20, 17(1976)).

PGI₂ has been confirmed to possess not only a very strong inhibitoryactivity on blood platelet aggregation but a dissociative activity onblood platelet aggregation, an inhibitory activity on blood plateletadhesion, a vasodilating activity, an inhibitory activity on gastricacid secretion etc. Therefore, it has been considered that PGI₂ isuseful for the prevention and/or the treatment for thrombosis,arteriosclerosis, ischemic heart diseases, gastric ulcer, hypertensionetc. But its application as a pharmaceutical is limited because of itschemical instability and the difficulty in separating the activitiesaccording to purpose. Accordingly, various PGI₂ derivatives have beensynthesized and much research has been carried out for the maintenanceand the separation of the activities. However, no satisfactory resultshave been obtained.

Recently, to solve two problems described above, research for PGI₂receptor agonists which have a new skeleton and which may be useful forthe treatment of or for the prevention of the above diseases, in view ofPGI₂ receptor level, has been carried out.

RELATED ARTS

It has been reported in the literature that the following compounds nothaving the PGI₂ skeleton are PGI₂ receptor agonists which bind to a PGI₂receptor and inhibit blood platelet aggregation: ##STR4## (see Brit. J.Pharmacol., 76, 423(1982), ibid, 84, 595(1985), and the Japanese PatentKohyo No. 55-501098), ##STR5## (see Brit. J. Pharmacol., 76, 423(1982),ibid, 84, 595(1985), and the Japanese Patent Kohyo No. 57-501127),##STR6## (see Brit. J. Pharmacol., 102, 251-266(1991) and the WestGerman Patent Publication No. 3,504,677), and ##STR7## (see U.S. Pat.No. 5,011,851).

PURPOSE OF THE INVENTION

Energetic investigation has been carried out to discover new PGI₂receptor agonists having a skeleton with a chemical structure differentfrom the compounds mentioned above. The present inventors have foundthat phenoxyacetic acid derivatives can bind to PGI₂ receptor and havean inhibitory activity on blood platelet aggregation.

The phenoxyacetic acid derivatives of formula (I), of the instantinvention are novel and it is not possible to predict from the abovecompounds known as PGI₂ receptor agonists, that the compounds of theinstant invention are PGI₂ receptor agonists.

DETAILED DISCLOSURE OF THE INVENTION

The present invention is related to:

1) Phenoxyacetic acid derivatives of the formula (I): ##STR8## wherein Ais i) --CR¹ ═N˜OR²,

ii) --CHR¹ --NH--OR²,

iii) --COE,

iv) --SO₂ E,

v) --CH₂ --NR³ --Y,

vi) --Z--NR³ --CONR⁴ R⁵,

vii) --CH₂ --OR⁶,

viii) --CO₂ R⁶,

ix) --CH₂ --O˜N═CR⁷ R⁸,

x) --CH₂ --O--NHCHR⁷ R⁸, ##STR9##

T is

i) single bond,

ii) C1-6 alkylene,

iii) C2-6 alkenylene or

iv) --O--(CH₂)_(s) --;

D is

i) --CO₂ R¹⁰ or

ii) --CONR¹¹ R¹² ;

E is

i) --NR⁴ R⁵,

ii) --NR³ OR⁶,

iii) --NR³ --NR⁴ R⁵ or

iv) --NR³ --N═CR⁴ R⁵ ;

Y is

i) --COR⁶,

ii) --CO--L--NR⁴ R⁵,

iii) --CS--NHR⁴ or

iv) --SO₂ R⁶ ;

Z is

i) --CH═N-- or

ii) --CH₂ --NR³ --;

L is single bond or C1-4 alkylene;

R¹ is hydrogen, C1-6 alkyl or phenyl;

R² is i) C1-8 alkyl substituted by one or two of phenyl, 4-7 memberedmonocyclic hetero ring containing one nitrogen or C4-7 cycloalkyl,

ii) C10-15 hydrocarbon condensed tricyclic ring or

iii) C1-15 alkyl;

R³ is hydrogen, C1-6 alkyl or phenyl;

R⁴ and R⁵ each, independently, is

i) hydrogen,

ii) phenyl,

iii) 4-7 membered monocyclic hetero ring containing one nitrogen or

iv) C1-4 alkyl substituted by one or two of phenyl or 4-7 memberedmonocyclic hetero ring containing one nitrogen;

R⁶ is

i) phenyl,

ii) 4-7 membered monocyclic hetero ring containing one nitrogen or

iii) C1-4 alkyl substituted by one to three of phenyl or 4-7 memberedmonocyclic hetero ring containing one nitrogen;

R⁷ is

i) hydrogen,

ii) C1-8 alkyl,

iii) phenyl or C4-7 cycloalkyl,

iv) 4-7 membered monocyclic hetero ring containing one nitrogen or

v) C1-4 alkyl substituted by one or two of phenyl, C4-7 cycloalkyl or4-7 membered monocyclic hetero ring containing one nitrogen;

R⁸ is

i) C1-8 alkyl,

ii) phenyl or C4-7 cycloalkyl

iii) 4-7 membered monocyclic hetero ring containing one nitrogen or

iv) C1-4 alkyl substituted by one or two of phenyl, C4-7 cycloalkyl or4-7 membered monocyclic hetero ring containing one nitrogen;

R⁹ is

i) hydrogen,

ii) phenyl,

iii) C1-4 alkyl or

iv) C1-4 alkyl substituted by one or two of phenyl or 4-7 memberedmonocyclic hetero ring containing one nitrogen;

R¹⁰ is hydrogen or C1-12 alkyl;

R¹¹ and R¹² each, independently, is hydrogen or C1-4 alkyl or

R¹¹ and R¹², taken together with nitrogen bond to R¹¹ and R¹² is theresidue of an amino acid;

R¹³ is hydrogen, C1-4 alkyl, C1-4 alkoxy or nitro;

m is 1-3,

n is 1-2,

s is 2-4;

and the rings of R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸ and R⁹ also may besubstitut ed by one to three of C1-C4 alkyl, C1-C4 alkoxy, halogen,nitro or trihalomethyl;

with the proviso that,

(1) when A is --SO₂ E wherein E is the same meaning hereinbeforedefined, T is not single bond and C1 alkylene (methylene),

(2) when A is ##STR10## where in R⁹ is the same meaning hereinbeforedefined, T is not C2-6 alkenylene; and non-toxic salts thereof andnon-toxic acid addition salts thereof.

2) Process for the preparation of them and

3) Pharmaceutical agent containing them as active ingredient.

Unless otherwise specified, all isomers are included in the invention.For example, alkyl, alkoxy, alkylene and alkenylene includes straightand branched ones. Double bond in alkenylene and oxime include E, Z andthe EZ mixture. Isomers generated by asymmetric carbon(s) e.g. branchedalkyl are included in the instant invention.

The compounds of formula (I) of the instant invention, wherein R¹⁰ ishydrogen, may be converted into the corresponding salts by methods knownper se. Non-toxic and water-soluble salts are preferable. Suitablesalts, for example, am salts of alkaline metals (potassium, sodium,etc.), salts of alkaline earth metals (calcium, magnesium, etc.),ammonium salts, salts of pharmaceutically-acceptable organic amines(tetramethylammonium, triethylamine, methylamine, dimethylamine,cyclopentylamine, benzylamine, phenethylamine, piperidine,monoethanolamine, diethanolamine, tris(hydroxymethyl)amine, lysine,arginine, N-methyl-D-glucamine) etc..

The compounds of formula (I) may be converted into the correspondingacid additional salts by methods known per se. Non-toxic andwater-soluble salts are preferable. Suitable acid addition salts, forexample, are salts of inorganic acids, e.g., hydrochloride,hydrobromide, sulphate, phosphate, nitrate etc., or salts of organicacids, e.g., acetate, lactate, tartarate, oxalate, fumarate, maleate,citrate, benzoate, methanesulphonate, ethanesulphonate,benzenesulphonate, toluenesulphonate, isethioate, glucuronate, gluconateetc.

The compounds of formula (I), salts thereof or acid additional saltsthereof may be converted into hydrates thereof by methods known per se.

In formula (I), C1-4 alkylene represented by L means methylene,ethylene, trimethylene, tetramethylene and isomeric groups thereof. C1-6alkylene represented by T means methylene, ethylene, trimethylene,tetrametylene, pentamethylene, hexamethylene and isomeric groupsthereof. C2-6 alkenylene represented by T means ethylene, trimethylene,tetramethylene, pentamethylene, hexamethylene and isomeric groupsthereof having one or two double bond.

In formula (I), C1-4 alkyl represented by R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹¹,R¹² and R¹³ means methyl, ethyl, propyl, butyl and isomeric groupsthereof. C1-6 alkyl represented by R¹ and R³ means methyl, ethyl,propyl, butyl, pentyl, hexyl and isomeric groups thereof. C1-8 alkylrepresented by R², R⁷ and R⁸ means methyl, ethyl, propyl, butyl, pentyl,hexyl, heptyl, octyl and isomeric groups thereof. C1-15 alkylrepresented by R² means methyl, ethyl, propyl, butyl, pentyl, hexyl,heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl,pentadecyl and isomeric groups thereof. C1-12 alkyl represented by R¹⁰means methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl,decyl, undecyl, dodecyl and isomeric groups thereof.

In formula (I), C1-4 alkoxy represented by R¹³ means methoxy, ethoxy,propoxy, butoxy and isomeric groups thereof.

In formula (I), C4-7 cycloalkyl represented by R², R⁷ and R⁸ means, forexample, cyclopentyl, cyclohexyl and cycloheptyl.

In formula (I), 4-7 membered monocyclic hetero ring represented by R²,R⁴, R⁵, R⁶, R⁷, R⁸ and R⁹ means, for example, pyrrole, pyridine, azepinering and partially or fully saturated ring thereof (e.g., pyrrolidine,piperidine ring, etc.).

In the formula (I), C10-15 hydrocarbon condensed tricyclic ring means,for example, indacene, fluorene, anthracene, dibenzocycloheptene ringsand partially or fully saturated ring thereof.

In formula (I), C1-C4 alkyl as substituents of the rings in R¹, R², R³,R⁴, R⁵, R⁶, R⁷, R⁸ and R⁹ mean methyl, ethyl, propyl, butyl and isomersthereof. C1-C4 alkoxy means methoxy, ethoxy, propoxy, butoxy and isomersthereof. Halogen and halogen in trihalomethyl means fluorine, chlorine,bromine and iodine atoms.

Examples of representative compounds of formula (I), of the instantinvention are:

(1) 3-[2-[2-Phenyl-2-(3-pyridyl)ethyl]oxyiminoethyl]phenoxyacetic acid,

(2) 3-[2-(2-Cyclohexyl-2-phenylethyl)oxyiminoethyl]phenoxyacetic acid,

(3) 3-[2-[2-(Fluorene-9-yl)ethyl]oxyiminoethyl]phenoxyacetic acid,

(4) 3-[2-(2-Phenyldecyl)oxyiminoethyl]phenoxyacetic acid,

(5) 4-(2-Benzoylaminoethyl)phenoxyacetic acid,

(6) 4-[2-(N,N-Diphenylaminocarbonylamino)ethyl]phenoxyacetic acid,

(7) 4-[2-(N,N-Diphenylaminomethylcarbonylamino)ethyl]phenoxyacetic acid,

(8) 4-(2-Phenylaminothiocarbonylaminoethyl)phenoxyacetic acid,

(9) 4-(2-Phenylsulfonylaminoethyl)phenoxyacetic acid,

(10) 4-[2-(N,N-Diphenylaminocarbonylaminoimino)ethyl]phenoxyacetic acid,

(11 ) 3-[3-(2-Diphenylmethylimidazol-5-yl)propyl]phenoxyacetic acid,

(12) 3-[3-(3,4,5-Triphenylpyrazol-1 -yl)propyl]phenoxyacetic acid,

(13) 3-[3-(Oxazol-2-yl)propyl]phenoxyacetic acid,

(14) 3-[3-(5-Ethyloxazol-4-yl)propyl]phenoxyacetic acid,

(15) 3-[3-[5-Di(3-pyridly)methylisoxazol-3-yl]propyl]phenoxyacetic acid,

(16) 3-[3-(4,5-Diphenylimidazolyl)propyl]phenoxyacetic acid,

(17) 3-[3-(5-Diphenylmethylisoxazol-3-yl)propyl]phenoxyacetamide,

(18) Amide of 3-[3-(5-Diphenylmethylisoxazol-3-yl)propyl]phenoxyaceticacid with glycine,

(19) Octyl 3-[3-(5-diphenyimethylisoxazol-3-yl)propyl]phenoxyacetate,

(20) 3-[3-[4-Di(3-pyridyl)methylpyrazol-1-yl]propyl]phenoxyacetic acid,

(21) 2-Methyl-3-[3-[4-[1 -phenyl-1-(3-pyridyl)methyl]pyrazol-1-yl]propyl]phenoxyacetic acid,

(22) 3-[3-Di(3-pyridyl)methyloxyiminopropyl]phenoxyacetic acid,

(23) 3-[3-[Di(3-pyridyl)methylideneaminooxy]propyl]phenoxyacetic acid,

(24) 3-[3-[1-cyclohexyl-1-Phenylmethylideneaminooxy]propyl]phenoxyaceticacid,

(25) 2-Methyl-3-[3-[1-phenyl-1 -(3-pyridyl)methylideneaminooxy]propyl]phenoxyacetic acid,

(26) 3-(3-Diphenylmethyloxyaminosulfonylpropyl)phenoxyacetic acid,

(27) 3-[3-[(N,N-Diphenylamino)aminosulfonyl]propyl]phenoxyacetic acid,

(28) 3-[3-[(1,1-Diphenylmethylideneamino)aminosulfonyl)propyl]phenoxyacetic acid,

(29) 4-[2-[(N,N-Diphenylaminocarbonylamino)amino]ethyl]phenoxyaceticacid,

(30)3-[3-[5-[1-Phenyl-1-(3-pyridyl)methyl]isoxazol-3-yl]propyl]phenoxyaceticacid,

(31)3-[4-Methyl-4-(1-phenyl-1-(3-pyridyl)methyloxyimino)butyl]phenoxyaceticacid,

(32)3-[2-[4-[1-Phenyl-1-(3-pyridyl)methyl]pyrazol-1-yl]ethyl]phenoxyaceticacid,

(33) 3-[3-[1-Phenyl-1-(3-pyridyl)methylaminooxy]propyl]phenoxyaceticacid,

non-toxic salts thereof, non-toxic acid addition salts thereof and thosedescribed in the examples below.

PROCESS FOR THE PREPARATION

The compounds of the instant invention of the formula (I), may beprepared:

(i) by reacting a compound of formula (III): ##STR11## wherein R^(10a)means methyl or ethyl and the other symbols have the same meaning ashereinbefore defined,

with a compound of formula (a):

    R.sup.2 ONH.sub.2                                          (a)

wherein R² has the same meaning as hereinbefore defined, p (ii) bysubjecting a compound obtained by reaction (i) of formula (Ia-1):##STR12## wherein all the symbols have the same meaning as hereinbeforedefined, to reduction,

(iii) by amidation of a compound of formula (IV): ##STR13## wherein allthe symbols have the same meaning as hereinbefore defined, with acompound of formula (b):

    H E                                                        (b)

wherein E has the same meaning as hereinbefore defined,

(iv) by subjecting a compound of formula (VI): ##STR14## wherein T^(a)is single bond, C1-4 alkylene, C2-4 alkenylene or --O--(CH₂)_(t) --wherein t is 0-2, and the other symbols have the same meaning ashereinbefore defined, to Jone's oxidation,

(v) by subjecting a compound obtained by reaction (iv) of formula(Ib-1): ##STR15## wherein all the symbols have the same meaning ashereinbefore defined, to hydrogenation (including a series of reactionssubjecting a compound of formula (Ib-1) to methylesterification, and tohydrogenation, followed by hydrolysis of the ester bond, for theconvenience of purification),

(vi) by amidation or thioamidation of a compound of formula (VIII):##STR16## wherein all the symbols have the same meaning as hereinbeforedefined, with a compound of formula (c):

    R.sup.6 CO.sub.2 H                                         (c)

wherein R⁶ have the same meaning as hereinbefore defined, or with acompound of formula (d):

    R.sup.4 R.sup.5 N--L--CO.sub.2 H                           (d)

wherein all the symbols have the same meaning as hereinbefore defined,or with a compound of formula (e):

    R.sup.4 --N═C═S                                    (e)

wherein R⁴ has the same meaning as hereinbefore defined, or with acompound of formula (f):

    R.sup.6 SO.sub.2 Cl                                        (f)

wherein R⁶ is the same meaning as hereinbefore defined,

(vii) by reacting a compound of formula (VII): ##STR17## wherein all thesymbols have the same meaning as hereinbefore defined, with a compoundof formula (g):

    H.sub.2 N--NR.sup.3 --CONR.sup.4 R.sup.5                   (g)

wherein all the symbols have the same meaning as hereinbefore defined,

(viii) by subjecting a compound obtained by reaction (vii) of formula(Ia-5): ##STR18## wherein all the symbols have the same meaning ashereinbefore defined, to reduction,

(ix) by reacting a compound obtained by reaction (viii) of formula(Ia-6): ##STR19## wherein all the symbols have the same meaning ashereinbefore defined, with a compound of formula (h):

    R.sup.3a I                                                 (h)

wherein R^(3a) is C1-6 alkyl or phenyl,

(x) by reacting a compound of formula (II): ##STR20## wherein all thesymbols have the same meaning as hereinbefore defined, with a compoundof formula (i): ##STR21## wherein R⁶ has the same meaning ashereinbefore defined, or with a compound of formula (s):

    R.sup.6 X                                                  (s)

wherein X has halogen and R⁶ is the same meaning as hereinbeforedefined,

(xi) by esterification of a compound of formula (IV): ##STR22## whereinall the symbols have the same meaning as hereinbefore defined, with acompound of formula (j):

    R.sup.6 OH                                                 (j)

wherein R⁶ has the same meaning as hereinbefore defined,

(xii) by reacting a compound of formula (IX): ##STR23## wherein all thesymbols have the same meaning as hereinbefore defined, with a compoundof formula (k):

    G H                                                        (k)

wherein G is ##STR24## wherein all the symbols have the same meaning ashereinbefore defined, or with a compound of formula (q):

    HO˜N═CR.sup.7 R.sup.8                            (q)

wherein all the symbols have the same meaning a hereinbefore defined, orwith a compound of formula (r):

    HO--NH--CHR.sup.7 R.sup.8                                  (r)

wherein all the symbols have the same meaning as hereinbefore defined,

(xiii) by reacting a compound of formula (x): ##STR25## wherein all thesymbols have the same meaning as hereinbefore defined, with a compoundof formula (I): ##STR26## wherein R⁹ has the same meaning ashereinbefore defined,

(xiv) by reacting a compound of formula (XII): ##STR27## wherein R^(9a)is phenyl, C1-4 alkyl or C1-4 alkyl substituted by one or two of phenylor 4-7 membered monocyclic hetero ring containing one nitrogen and theother symbols have the same meaning as hereinbefore defined, or acompound of formula (XIV): ##STR28## wherein all the symbols have thesame meaning as hereinbefore defined, or a compound of formula (XVII):##STR29## wherein all the symbols have the same meaning as hereinbeforedefined, or a compound of formula (XXIII): ##STR30## wherein all thesymbols have the same meaning as hereinbefore defined, or a compound offormula (XXIX): ##STR31## wherein all the symbols have the same meaningas hereinbefore defined, with a compound of formula (m):

    BrCH.sub.2 CO.sub.2 R.sup.10a                              (m)

wherein R^(10a) has the same meaning as hereinbefore defined,

(xv) by reacting of a compound of formula (XV): ##STR32## wherein allthe symbols have the same meaning as hereinbefore defined, with acompound of formula (n):

    R.sup.9 COCl                                               (n)

wherein R⁹ has the same meaning as hereinbefore defined,

(xvi) by cyclization of a compound of formula (XVIII): ##STR33## whereinall the symbols have the same meaning as hereinbefore defined,

(xvii) by cyclization of a compound of formula (XX): ##STR34## whereinall the symbols have the same meaning as hereinbefore defined,

(xviii) by hydrolysis of a compound obtained by hereinbefore reaction(i), (ii), (iii), (vi), (vii), (viii), (ix), (x), (xi), (xii), (xiii),(xiv), (xv), (xvi) or (xvii) of formula (Ia): ##STR35##

wherein A^(a) is

i) --CR¹ ═N˜OR²,

ii) --CHR¹ --NH--OR²,

iii) --COE,

iv) --CH₂ NR³ --Y,

v) --CH═N--NR³ --CONR⁴ R⁵,

vi) --CH₂ --NH--NR³ --CONR⁴ R⁵,

vii) --CH₂ --NR^(3a) --NR³ --CONR⁴ R⁵,

viii) --CH₂ OR⁶,

ix) --CO₂ R⁶,

x) --CH₂ G,

xi) --CH₂ --O˜N═CR⁷ R⁸,

xii) --CH₂ --O--NHCHR⁷ R⁸, ##STR36## and the other symbols have the samemeaning as hereinbefore defined,

(xix) by esterification of a compound obtained by hereinbefore reaction(iv), (v) or (xviii) of formula (Ib): ##STR37## wherein all the symbolshave the same meaning as hereinbefore defined, with a compound offormula (o):

    R.sup.10b OH                                               (o)

wherein R^(10b) is C1-12 alkyl, or

(xx) by amidation of a compound obtained hereinbefore by reaction (iv),(v) or (xviii) of formula (Ib): ##STR38## wherein all the symbols havethe same meaning as hereinbefore defined, with a compound of formula(p):

    R.sup.11 R.sup.12 NH                                       (p)

wherein all the symbols have the same meaning as hereinbefore defined.

The reaction (i) is known, for example, it may be carried out in aninert organic solvent (tetrahydrofuran (THF), methanol, ethanol,dimethoxyethane, dioxane, mixtures thereof etc.) at 0°-70° C.

The reactions (ii) and (viii) are known, for example, they may becarried out in a water miscible organic solvent (THF, dioxane, methanol,ethanol, dimethoxyethane mixtures thereof etc.), in the presence of anacid (hydrochloric acid, acetic acid, trifluoroacetic acid etc.) using areducing agent (sodium cyanoborohydride etc.) at 0°-70° C.

The reactions (iii) and (vi) are known, for example, they may be carriedout in an inert organic solvent (methylene chloride etc.), in thepresence of an appropriate condensing agent (2-chloro-N-methylpyridinumiodide etc.) and a proper base (triethylamine,N,N-dimethylaminopyridine, mixtures thereof etc.) at 0°-40° C.

The reaction (iv) is known, for example, it may be carried out inacetone using a Jone's agent at -10°-40° C.

The reaction (v) is known, for example, it may be carried out in aninert organic solvent (THF, diethylether, dioxane, ethyl acetate,methanol, ethanol, methylene chloride etc.) using a catalyst (palladiumon carbon, palladium, hydoxy palladium, palladium acetic acid, palladiumblack, platinum black etc.) at normal or elevated pressures of hydrogengas, at 0°-80° C.

The reaction may be carried out, for the convenience of purification, byexposing a compound of formula (Ib-1) to methylestification and tohydrogenation, following hydrolysis of an ester bond. Themethylestification is known, for example, it may be carried out in aninert organic solvent (diethylether, ethyl acetate etc.) usingdiazomethane at 0°-10° C. The hydolysis of an ester bond may be carriedout by the same procedure as hereafter defined for reaction (xviii).

The reaction (vii) is known, for example, it may be carried out in aninert organic solvent (methanol, ethanol etc.) under an atmosphere ofinert gas at 0°-40° C.

The reaction (ix)is known, for example, it may be carried out in aninert organic solvent (N,N-dimethylformamide (DMF), etc.) in thepresence or absence of an appropriate base (sodium hydride etc.).

The reaction (x) is known, for example, it may be carried out in aninert organic solvent (chloroform, cyclohexane, mixtures thereof etc.),in the presence of a Lewis acid (trifluoroborane etherate etc.), or inan inert organic solvent (DMF etc.), in the presence of an amine(N,N-dimethylaminopyridine, triethylamine, pyridine etc.) at 0° C.--areflux temperature.

The reaction (xi) is known, for example, it may be carried out in aninert organic solvent (methylene chloride etc.) in the presence of anappropriate condensing agent (2-chloro-N-methylpyridinum iodide etc.)and a proper base (triethylamine, N,N-dimethylaminopyridine, mixturesthereof etc.) at 0°-0° C.

The reaction (xii) is known, for example, it may be carried out in inertorganic solvent (DMF, THF, etc.) in the presence of an appropriate base(sodium hydride, potassium t-butoxide, n- butyllithium, etc.).

The reaction (xiii) is known, for example it may be carried out in aninert organic solvent (chloroform, etc.) at 0° C.--a reflux temperature.

The reaction (xiv) is known for example, it may be carried out in aninert organic solvent (DMF, acetone, etc.), in the presence of anappropriate base (potassium carbonate etc.) at 0°-50° C.

The reaction (xv) is known it may be carried out at 80°-135° C. withoutan organic solvent.

The reactions (xvi) and (xvii) are known, for example, they may becarried out in an inert organic solvent (truene etc.) at 0° C.--a refluxtemperature.

The reaction (xviii) is known, for example, it may be carried out in aninert organic solvent (methanol, ethanol, dioxane, THF, dimethoxyethane,mixtures thereof etc.) using an aqueous alkali solution (potassiumhydroxide, sodium hydroxide, potassium carbonate, sodium carbonate etc.)at 0°-50° C.

The reactions (xix) and (xx) are known, for example, they may be carriedout by reacting a compound of the formula (Ib) in an inert organicsolvent (methylene chloride etc.) with an acyl halide such as oxalylchloride, thionyl chloride and then by reacting a compound thus obtainedwith an alcohol of formula (o) or an amine of formula (p), respecitvelyin an inert organic solvent (methylene chloride, etc.), in the presenceof an appropriate base (triethylamine etc.) at 0°-40° C.

Compounds of formulae (III), (VI), (VIII), (IX), (X), (XII), (XIV),(XV), (XVII), (XVIII) and (XX) may be prepared using a series ofreactions depicted in the following schemes. ##STR39##

In the schemes,

R^(9b) is

(i) hydrogen,

(ii) phenyl,

(iii) C1-4 alkyl or

(iv) C1-4 alkyl substituted by one or two tings optionally selected fromphenyl or 4-7 membered monocyclic hetero ring containing one nitrogenand/or one hydroxyl

R^(9c) has same meaning as R^(9b) provided that the hydroxy in R^(9b) isreplaced by --OLi;

and the other symbols have the same meaning as hereinbefore defined;

PDC is pyridinium dichromate;

THP is tetrahydropyran-2-yl;

DMF is N,N-dimethylformamide;

THF is tetrahydrofuran;

HMPA is hexamethylphosphoramide;

TEA is triethylamine;

DBU is 1,8-diazabicyclo [5, 4, 0]-7-undecene;

DEAD is diethylazocarboxylate;

DHP is dihydropyran;

DME is dimethoxyethane; and

TBAB is n-tetrabutylammonium bromide.

In each reaction in the instant specification, products may be purifiedby conventional manner. For example, it may be carried out by adistillation at atmospheric or reduced pressure, high performace liquidchromatography, thin layer chromatography or column chromatography usingsilica gel or magnesium silicate, washing or recrystallization.Purification may be carried out after each reaction or after a series ofreactions.

The starting materials and reagents in the processes for preparing theinstant compounds are known per se, or may be prepared by methods knownper se.

PHARMACOLOGIC ACTIVITIES

It has been confirmed that the compounds of the instant invention offormula (I) possess an agonistic activity at the PGI₂ receptor by thefollowing experimental results.

i) Inhibitory activity on binding of [³ H]-iloprost to PGI₂ receptor inthe human blood platelet membrane fraction

METHOD

50 mM Tris-HCl buffer (pH 7.4) containing 15 mM MgCl₂, 5 mM EDTA and 10nM [³ H]-iloprost were used as reaction medium. To 0.2 ml of thereaction medium, human blood platelet membrane fraction (0.3 mg protein)was added with or without a test compound. The mixture was incubated at24° C. for 30 min. After incubation, 4 ml of ice-cold 10 mM Tris-HClbuffer (pH 7.4) was added to the reaction mixture, the mixture wasfiltered through Whatman GF/B glass fiber filter and washed 4 times with4 ml of ice-cold 10 mM Tri-HCl buffer (pH 7.4) to separate bound andfree [³ H]-iloprost. After washing, the filter was dried andradioactivity was counted. Non-specific binding was obtained byperforming parallel binding experiments in the presence of 10 μMnon-labelled iloprost. Specific binding was calculated by subtractingthe non-specific binding from the total binding.

The inhibitory effect of a test compound was calculated from thefollowing equation.

The percentage of inhibition (%)=100-(B₁ /B₀ ×100)

B₁ :specific [³ H]-iloprost binding in the presence of a test compound

B₀ :specific [³ H]-iloprost binding in the absence of a test compound

The results are shown in the following Table 1.

                  TABLE 1                                                         ______________________________________                                        Example No.    IC.sub.50 (μM)                                              ______________________________________                                         2             4.8                                                             4             1.6                                                             6             3.0                                                             8(l)          1.5                                                             8(n)          2.0                                                             8(o)          0.46                                                           12             1.3                                                            15             4.0                                                            17             0.15                                                           17(b)          0.36                                                           17(c)          0.27                                                           17(i)          0.22                                                           17(n)          2.0                                                            17(s)          0.78                                                           17(x)          5.0                                                            17(cc)         0.26                                                           19             0.12                                                           21             4.4                                                            23             1.5                                                            ______________________________________                                    

ii) Inhibitory effect on human blood platelet aggregation

METHOD

Platelet-rich plasma (PRP) was prepared from human blood (5×10⁵platelets/mm³) and a test compound was added to PRP 1 minute prior tothe addition of ADP (4 μm). The aggregation was monitored using aplatelet aggregometer (NBS HEMA TRACER 601, Niko Bioscience, Japan).

The results are shown in the following Table 2.

                  TABLE 2                                                         ______________________________________                                        Example No.    IC.sub.50 (μM)                                              ______________________________________                                         4             3.7                                                             8(n)          3.1                                                             8(o)          0.97                                                           12             5.0                                                            17             0.42                                                           17(b)          0.24                                                           17(c)          0.47                                                           17(s)          3.2                                                            17(cc)         0.41                                                           19             0.16                                                           23             0.37                                                           ______________________________________                                    

TOXICITY

The toxicity of the compounds of the instant invention of formula (I) isvery low and therefore, it may be confirmed that the compounds of theinstant invention are fully safe for pharmaceutic use.

APPLICATION FOR PHARMACEUTICS

The compounds of the instant invention of formula (I) possess anagonistic activity on the PGI₂ receptor, and therefore are useful forthe prevention and/or the treatment of thrombosis, arteriosclerosis,ischemic heart diseases, gastric ulcer, hypertension, etc.

For the purpose described above, the compounds of formula (I) of theinstant invention, non-toxic salts thereof, acid additional saltsthereof and hydrates thereof may be administered normally systemicallyor partially, usually by oral or parenteral administration.

The doses to be administered are determined depending on age, bodyweight, symptom, the desired therapeutic effect, the route ofadministration, the duration of the treatment etc. In the human adult,the doses per person per dose are generally between 1 mg and 1000 mg, byoral administration, up to several times per day, and between 100 μg and100 mg, by parenteral administration up to several times per day, orcontinuous administration between 1 and 24 hrs. per day via a vein.

As mentioned above, the doses to be used depend on various conditions.Therefore, there are cases in which doses lower than or greater than theranges specified above may be used.

When administering a compound of the instant invention, it is used assolid compositions, liquid compositions, other compositions for oraladministration, as liniments, as suppositories etc. and for parenteraladministration.

Solid compositions for oral administration include compressed tablets,pills, capsules, dispersible powders and granules. Capsules include hardcapsules and soft capsules.

In such compositions, one or more of the active compound(s) is or areadmixed with at least one inert diluent (such as lactose, mannitol,glucose, hydroxypropyl cellulose, microcrystalline cellulose, starch,polyvinylpyrrolidone, magnesium metasilicate aluminate etc.). Thecompositions also may comprise, as is normal practice, additionalsubstances other than inert diluents: e.g. lubricating agents (such asmagnesium stearate etc.) disintegrating agents (such as cellulosecalcium glycolate, etc.), stabilizing agents (such as lactose, etc.) andassisting agents for dissolving such as glutamic acid etc.).

The tablets or pills may, if desired, be coated with a film of gastricor enteric material (such as sugar, gelatin, hydroxypropyl cellulose,hydroxypropylmethyl cellulose phtalate etc.), or may be coated with morethan two films. Further coating may include containment within capsulesof absorbable materials such as gelatin.

Liquid compositions for oral administration includepharmaceutically-acceptable solutions, emulsions, suspensions, syrupsand elixirs. In such compositions, one or more of the acitve compound(s)is or are contained in inert diluent(s) commonly used in the art(Purified water, ethanol etc.). Besides inert diluents, suchcompositions also may comprise adjuvants (such as wetting agents,suspending agents etc.), sweetening agents, flavouring agents, perfumingagents and preserving agents.

Other compositions for oral administration included spray compositionswhich may be prepared by known methods and which comprise one or more ofthe active compound(s). Spray compositions may comprise additionalsubstances other than inert diluents: e.g. stabilizing agents (sodiumsulfate etc.), isotonic buffer(sodium chloride, sodium citrate, citricacid etc.). For preparation of such spray compositions, for example, themethod described in U.S. Pat. No. 2,868,691 or 3,095,355 (hereinincorporated in entirety by reference) may be used.

Injections for parenteral administration include sterile aqueous ornon-aqueous solutions, suspensions and emulsions. In such compositions,one more of active compounds(s) is or are admixed with at least one ofinert aqueous diluent(s) (distilled water for injection, physiologicalsalt solution etc.) or inert non-aqueous diluent(s) (propylene glycol,polyethylene glycol, olive oil, ethanol, POLYSORBATE80 (registered trademark) etc.).

Injections may comprise additional other inert diluents: e.g. preservingagents, wetting agents, emulsifying agents, dispersing agents,stabilizing agent (lactose, etc.), assisting agents such as assistingagents for dissolving (glutamic acid, asparaginic acid, etc.).

They may be sterilized for example, by filtration through abacteria-retaining filter, by incorporation of sterilizing agents in thecompositions or by irradiation. They also may be manufactured in theform of sterile solid compositions, for example, by freeze-drying, andwhich may be dissolved in sterile water or some other sterile diluent(s)for injection immediately before use.

Other compositions for parenteral administration include liquids forexternal use, endermic liniments, ointment, suppositories and pessarieswhich comprise one or more of the active compound(s) and may be preparedby per se known methods.

REFERENCE EXAMPLES AND EXAMPLES

The following reference examples and examples illustrate the instantinvention, but do not limit the present invention.

The solvents in parentheses show the developing or eluting solvents andthe ratios of the solvents used are by volume in chromatographicseparations.

Unless otherwise specified, "IR" were measured by the liquid film methodand "NMR" were measured in a solution of CDCl₃.

Reference example 1 Methyl 3-(3-formylpropyl)phenoxyacetate ##STR40##

To a solution of oxalyl chloride (1.26 ml) in methylene chloride (30 ml)at -70° C., a solution of dimethylsulfoxide (2.11 ml) in methylenechloride (3.0 ml) was added dropwise. To the obtained solution, asolution of methyl 3-(4-hydroxybutyl) phenoxyacetate (1.94 g) inmethylene chloride (8.0 ml) was added dropwise. Triethylamine (6.9 ml)was added dropwise thereto while the reaction temperature was maintainedat -70° C. The reaction mixture was warmed slowly to -40° C. over a 30min period and then quenched by addition of a saturated aqueous solutionof ammonium chloride. The reaction mixture was extracted with ether. Theextract was washed with a saturated aqueous solution of ammoniumchloride and a saturated aqueous solution of sodium chloride,successively, dried over anhydrous magnesium sulfate and evaporated. Theresidue was purified by silica gel column chromatography (n-hexane:ethylacetate=5:2) to give the title compound (1.41 g) having the followingphysical data.

TLC: Rf 0.26 (n-hexane:ethyl acetate=2:1);

NMR: δ9.74 (1H, s), 7.35-7.07(1H, m), 6.92-6.60 (3H, m), 4.62 (2H, s),3.79 (3H, s), 2.63 (2H, t, J=7Hz), 2.47 (2H, t, J=8Hz), 2.10-1.92 (2H,m).

Reference example 2 Methyl 3-(4-hydroxyheptyl)phenoxyacetate ##STR41##

To a solution of the compound prepared in reference example 1 (1.26 g)in diethyl ether (10 ml), n-propylmagnesium bromide (3.0 ml of 2M indiethyl ether) was added dropwise at -70° C. The reaction mixture wasstirred for 2 h with warming. After being quenched by addition of asaturated aqueous solution of ammonium chloride, the mixture wasextracted with ether. The extract was washed with a saturated aqueoussolution of sodium chloride, dried over anhydrous magnesium sulfate andevaporated. The residue was purified by silica gel column chromatography(n-hexane:ethyl acetate=2:1) to give the title compound (820 mg) havingthe following physical data.

TLC: Rf 0.23 (n-hexane:ethyl acetate=2:1);

NMR: δ7.36-7.08 (1H, m), 6.95-6.60 (3H, m), 4.64 (2H, s), 3.82 (3H, s),3.80 -3.50 (1H, m), 2.80-2.36 (3H, m), 2.20-1.25 (8H, m), 1.10-0.80 (3H,m).

Reference example 3 Methyl 3-(4-oxoheptyl)phenoxyacetate ##STR42##

Pyridium dichromate (2.53 g) was added to a solution of the compoundprepared in reference example 2 (750 mg) in dimethylformamide (10 ml) atroom temperature. The mixture was stirred overnight. Celite (registeredtrade mark) and Florisil (registerd trade mark) were added to themixture. The mixture was diluted with a mixture of n-hexane ethylacetate (3:1)(20 ml). The mixture was filtered through Florisil and thefiltrate was evaporated. The residue was purified by silica gel columnchromatography (n-hexane: ethyl acetate=5:1) to give the title compound(350 mg) having the following physical data.

TLC: Rf 0.30 (n-hexane:ethyl acetate=3:1);

NMR: δ7.36-7.08 (1H, m), 6.90-6.60 (3H, m), 4.62 (2H, s), 3.81 (3H, s),2.72-2.25 (6H, m), 2.10-1.38 (4H, m), 0.90 (3H, t, J=8Hz).

Reference example 43-[3-[2-(tetrahydropyran-2-yl)oxyethoxy]phenyl]propanol ##STR43##

To a suspension of sodium hydride (1.84 g, 60% dispersion) indimethylformamide (50 ml) was added dropwise a solution of3-(3-hydroxypropyl)phenol (7.0 g)in dimethylformamide (20 ml) at 0° C.The mixture was stirred for 1 h at room temperature. To the reactionmixture was added 1-bromo-2-(tetrahydropyran-2-yl)ethane (5.46 g) at 0°C. The mixture was stirred for 1 h at room temperature. After beingquenched by addition of water, the mixture was extracted with ether. Theextract was washed with 2N aqueous solution of sodium hydroxide, waterand a saturated aqueous solution of sodium chloride, successively, driedover anhydrous magnesium sulfate and evaporated. The residue waspurified by silica gel column chromatography (ethylacetate:n-hexane=1:2→2:1) to give the title compound (3.36 g) having thefollowing physical data.

TLC: Rf 0.17 (ethyl acetate:n-hexane=1:2);

IR(cm⁻¹): ν3369, 2930, 1584, 1488, 1451, 1384, 1353, 1260, 1202, 1125,1034, 992,874, 814, 777, 695.

Reference example 51-[2-(Tetrahydropyran-2-yl)oxyethoxy]-3-(3-hydroxy-4-diphenylaminosulfonylbutyl)benzene ##STR44##

To a solution of N,N-diphenylsulfonamide (0.99 g) in a mixture oftetrahydrofuran-hexamethylphosphoramide (20:3) (23 ml) was addeddropwise n-butyllithium (3.75 ml of 1.6M in n-hexane) at -78° C. Themixture was stirred for 30 min at -78° C. To the mixture obtained wasadded a solution of a compound (which was prepared by the same procedureas reference example 1, using the compound prepared in reference example4) (1.11 g) in tetrahydrofuran (10 ml). The reaction mixture was stirredfor 1 h at -78° C. After quenched by addition of water, the mixture wasextracted with ethyl acetate. The extract was washed with water and asaturated aqueous solution of sodium chloride, successively, dried overanhydrous magnesium sulfate and evaporated. The residue was purified bysilica gel column chromatography (ethyl acetate:n-hexane=1:2) to givethe title compound (0.84 g) having the following physical data.

TLC: Rf 0.37 (ethyl acetate:benzene=1:1);

IR(cm⁻¹): ν3401, 3063, 2930, 1586, 1489, 1451, 1351, 1261, 1190, 1150,1077, 1050, 1011, 969, 903, 822, 757, 697.

Reference example 6 1-[2-(Tetrahydropyran-2-yl)oxyethoxy]-3-(3-methylsulfonyloxy-4-diphenylaminosulfonylbutyl)benzene##STR45##

To a solution of the compound prepared in reference example 5 (0.66 g)in methylene chloride (20 ml) were added successively triethylamine(0.305 g) and methanesulfonyl chloride (0.12 ml) at 0° C. The mixturewas stirred for 10 min at same temperature. After quenched by additionof water, the mixture was extracted with ethyl acetate. The extract waswashed with a saturated aqueous solution of ammonium chloride, water anda saturated aqueous solution of sodium chloride, successively, driedover anhydrous magnesium sulfate and evaporated. The residue containingthe title compound having the following physical data. The residue wasused for the next reaction without further purification.

TLC: Rf 0.31 (ethyl acetate:benzene=1:8).

Reference example 71-[2-(Tetrahydropyran-2-yl)oxyethoxy]-3-(4-diphenylaminosulfonyl-3-butenyl)benzene##STR46##

To a solution of the residue obtained in reference example 6 in benzenewas added 1, 8-diazabicyclo[5, 4, 0]-7-undecene (0.382 g) at 0° C. Themixture was stirred for 10 min at 0° C. After quenched by addition ofwater, the mixture was extracted with ethyl acetate. The extract waswashed with a saturated aqueous solution of ammonium chloride, water anda saturated aqueous solution of sodium chloride, successively, driedover anhydrous magnesium sulfate and evaporated to give the titlecompound (0.63 g) having the following physical data.

TLC: Rf 0.27 (ethyl acetate:benzene=1:8);

IR (cm-⁻¹): ν3063, 2943, 2873, 1734, 1586, 1489, 1451, 1354, 1260, 1152,1126, 1076, 1034, 989, 969, 904, 874, 816,757, 697.

Reference example 82-[3-(4-Diphenylaminosufonyl-3-butenyl)phenoxy]ethanol ##STR47##

To a solution of the compound prepared in reference example 7 (0.541 g)in methanol (20 ml) was added a catalytic amount of 10-camphorsulfonicacid (dl form) at room temperature. The mixture was stirred for 1 h atroom temperature. To the reaction mixture was added triethylamine (0.1ml) the mixture was evaporated. The residue was purified by silica gelcolumn chromatography (ethyl acetate:n-hexane=1:2→1:1) to give the titlecompound (0.404 g) having the following physical data.

TLC: Rf 0.37 (ethyl acetate:benzene=1:1);

IR(cm-⁻¹): ν3401, 3063, 2930, 1586, 1489, 1451, 1351, 1261, 1190, 1150,1077, 1050, 1011, 969, 903, 822, 757, 697.

Reference example 9 Methyl 3-(3-bromopropyl)phenoxyacetate ##STR48##

To a stirred solution of methyl 3-(3-hydroxypropyl)phenoxyacetate (2.00g) in methylene chloride (20 ml) were added successivelytriphenylphosphine (2.81 g) and tetrabromomethane (3.55 g) at roomtemperature. The mixture was evaporated. The residue was purified bysilica gel column chromatography (n-hexane:ethyl acetate=7:1) to givethe title compound (1.69 g) having the following physical data.

TLC: Rf 0.26 (n-hexane:ethyl acetate=2:1);

NMR: δ7.30-7.06 (1H, m), 6.90-6.60 (3H, m), 4.63 (2H, s), 3.81 (3H, s),3.38 (2H, t, J=8Hz), 2.76 (2H, t, J=8Hz), 2.32-1.96 (2H, m).

Reference example 10 1-Benzyloxy-3-(3-benzyloxycarbonylpropyl)benzene##STR49##

A mixture of 1-hydroxy-3-(3-benzyioxycarbonylpropyl)benzene (2.0 g),benzylbromide (1.14 ml), potassium bicabonate (1.53 g) anddimethylformamide (20 ml) was stirred for 3 h at room temperature. Themixture was quenched by addition of water and extracted with a mixtureof n-hexane:ethyl acetate (3:1). The extract was washed with water and asaturated aqueous solution of sodium chloride, successively, dried overanhydrous magnesium sulfate and evaporated. The residue was purified bysilica gel column chromatography (n-hexane:ethyl acetate=10:1) to givethe title compound (2.55 g) having the following physical data.

TLC: Rf 0.33 (n-hexane:ethyl acetate=7:1);

IR(cm⁻¹): ν3065, 3033, 2939, 2866, 1734, 1583, 1489, 1455, 1382, 1315,1258, 1156, 1082, 1027, 908, 850, 777, 739.

Reference example 11 4-(3-Benzyloxyphenyl)butanoic acid ##STR50##

To a solution of the compound prepared in reference example 10 (2.42 g)in a mixture of tetrahydrofuran-methanol (2:1) (20 ml) was added 2Naqueous solution of sodium hydroxide (11 ml) at 0° C. The mixture wasstirred for 3 h at room temperature. After neutralized by addition of 2Naqueous solution of hydrochloric acid, the mixture was extracted withethyl acetate. The extract was washed with water and a saturated aqueoussolution of sodium chloride, successively, dried over anhydrousmagnesium sulfate and evaporated. The residue was recrystallized fromn-hexane-ethyl acetate to give the title compound (1.5 g) having thefollowing physical data.

mp.: 100.0°-102.0° C.;

TLC: Rf 0.53 (ethyl acetate);

NMR: δ7.50-7.08 (7H, m), 6.93-6.70 (3H, m), 5.04 (2H, s), 2.66 (2H, t,J=7Hz), 2.36 (2H, t, J=8Hz), 2.16-1.93 (2H, m).

Reference example 121-Benzyloxy-3-[3-(N-methyl-N-methoxyamino)carbonylpropyl]benzene##STR51##

An ethyl chloroformate (0.96 ml) was dissolved with stirring of asolution of the compound prepared in reference example 11 (2.45 g) andtriethylamine (1.35 ml) in methylene chloride (30 ml) at -10° C. Afterstirred for 10 min at room temperature, to the mixture were addedsuccessively triethylamine (2.8 ml) and N-methyl-N-methoxyaminehydrochloride (980 mg) at -10° C. The mixture was stirred further for 1h at room temperature and was poured into water. The mixture wasextracted with a mixture of n-hexane-ethyl acetate (1:1). The extractwas washed with water and a saturated aqueous solution of sodiumchloride, successively, dried over anhydrous magnesium sulfate andevaporated. The residue was purified by silica gel column chromatography(n-hexane:ethyl acetate=2:1) to give the title compound (2.67 g) havingthe following physical data.

TLC: Rf 0.23 (n-hexane:ethyl acetate=2:1);

NMR: δ7.48-7.03 (6H, m), 6.86-6.67 (3H, m), 5.04 (2H, s), 3.61 (3H, s),3.16 (3H, s), 2.78-2.30 (4H, m), 2.12-1.80 (2H, m).

Reference example 131-Benzyloxy-3-(3-hydroxy-3,3-diphenyl-1-propynyl)carbonylpropyl benzene##STR52##

To a solution of 1,1-diphenyl-2-propyn-1-ol (3.89 g) in tetrahydrofuran(40 ml) was added n-butyllithium (23.4 ml of 1.6M in n-hexane) at -78°C. After being stirred for 30 min at the same temperature, to themixture was added boron trifluoride etherate (5.05 ml). The mixture wasstirred for 30 min at -78° C. To the mixture, the compound prepared inreference example 12 (2.67 g) in tetrahydrofuran (20 ml) was added atsame temperature. After being stirred for 1 h at -78° C., the reactionmixture was quenched by addition of a saturated aqueous solution ofammonium chloride and the mixture stirred for 30 rain at roomtemperature. The mixture was extracted with a mixture of n-hexane-ethylacetate (3:1). The extract was washed with water and a saturated aqueoussolution of sodium chloride, successively, dried over anhydrousmagnesium sulfate and evaporated. The residue was purified by silica gelcolumn chromatography (n-hexane:ethyl acetate=7:1) to give the titlecompound (2.8 g) having the following physical data.

mp.: 54.5°-56.0° C.

TLC: Rf 0.18 (n-hexane:ethyl acetate=6:1);

NMR: δ7.45-7.10 (16H, m), 6.86-6.71 (3H, m), 5.01 (2H, s), 3.00 (1H, s),2.68 -2.53 (4H, m), 2.10-1.90 (2H, m).

Reference example 141-Benzyloxy-3-[3-(5-hydroxydiphenylmethylisoxazole-3-yl)propyl]benzene##STR53##

A mixture of the compound prepared in reference example 13 (1.0 g),hydroxyamine hydrochloride (1.5 g), pyridine (10 ml) and ethanol (10 ml)was refluxed for 6 h. The mixture was concentrated under reducedpressure and the reside was quenched by addition of water. The mixturewas extracted with ethyl acetate. The extract was washed with asaturated aqueous solution of sodium chloride, dried over anhydrousmagnesium sulfate and evaporated. The residue was purified by silica gelcolumn chromatography (n-hexane:ethyl acetate=7:1) to give the titlecompound (940 mg) having the following physical data.

mp.: 89.0°-90.5° C.;

NMR: δ7.43-7.16 (16H, m), 6.80-6.74 (3H, m), 5.80 (1H, s), 5.03 (2H, s),3.17 (1H, s), 2.67-2.61 (4H, m), 2.00-1.90 (2H, m).

Reference example 151-Benzyloxy-3-[3-(5-diphenylmethylisoxazol-3-yl)propyl]benzene ##STR54##

To a solution of the compound prepared in reference example 14 (860 mg)in trifluoroacetic acid (8.0 ml) was added a solution of triethylsilane(440 mg) in methylene chloride (2.0 ml) with stirring at 0° C. Afterstirring for 30 min at room temperature, the mixture was concentratedunder reduced pressure. The residue was neutralized with a saturatedaqueous solution of sodium bicarbonate and extracted with ethyl acetate.The extract was washed with water and a saturated aqueous solution ofsodium chloride, successively, dried over anhydrous magnesium sulfateand evaporated. The residue was purified by silica gel columnchromatography (n-hexane:ethyl acetate=8:1) to give the title compound(640 mg) having the following physical data.

TLC: Rf 0.50 (n-hexane:ethyl acetate=3:1);

NMR: δ7.50-7.00 (16H, m), 6.85-6.65 (3H, m), 5.70 (1H, s), 5.30 (1H, s),5.03 (2H, s), 2.80-2.50 (4H, m), 2.17-1.75 (2H, m).

Reference example 161-Hydroxy-3-[3-(5-diphenylmethylisoxazol-3-yl)propyl]benzene ##STR55##

To a solution of the compound prepared in reference example 15 (550 mg)in methylene chloride (6.0 ml) was added boron tribromide (0.34 ml) withstirring at 0° C. The mixture was stirred for 30 min at 0° C., pouredinto ice water and extracted with ethyl acetate. The extract was washedwith water and a saturated aqueous solution of sodium chloride,successively, dried over anhydrous magnesium sulfate and evaporated. Theresidue was purified by silica gel column chromatography (n-hexane:ethylacetate=5:1→3:1) to give the title compound (376 mg) having thefollowing physical data.

mp.: 114.5°-117° C.;

TLC: Rf 0.22 (n-hexane:ethyl acetate=3:1);

NMR: δ7.39-7.05 (11H, m), 6.75-6.60(3H, m), 5.73 (1H, s), 5.62-5.53 (1H,m), 5.52 (1H, s), 2.70-2.52 (4H, m), 2.02-1.84 (2H, m).

Reference example 17 Methyl 3-[3-[(1-amino-2,2-diphenylethylidene)aminooxycarbonyl]propyl]phenoxyacetate ##STR56##

A suspension of 4-(3-methoxycarbonylmethoxyphenyl)butanoic acid (289 mg)and thionyl chloride (5.0 ml) was refluxed for 1 h. The mixture wascooled to room temperature and concentrated under reduced pressure. To asuspension of the residue and 1,1-diphenyl-2-amino-2-hydroxyiminoethane(285 mg)in methylene chloride (5 ml) was added tiethylamine (0.32 ml)with stirring at room temperature. The mixture was stirred overnight atroom temperature. After quenched by addition of water, the mixture wasextracted with ether. The extract was washed with water and a saturatedaqueous solution of sodium chloride, successively, dried over anhydrousmagnesium sulfate and evaporated. The residue was purified by silica gelflash chromatography (n-hexane:ethyl acetate=1:1) to give the titlecompound (193 mg) having the following physical data.

NMR: δ7.40-7.00 (11H, m), 6.90-6.50 (3H, m), 5.26 (1H, s), 4.75 (2H,brs), 4.58 (2H, s), 3.78 (3H, s), 2.64 (2H, t, J=7Hz), 2.40 (2H, t,J=7Hz), 2.00 (2H, m);

MS (m/z): 461 (M⁺ +1).

Reference example 18 Methyl 3-(3-cyanopropyl)phenoxyacetate ##STR57##

A mixture of potassium cyanide (1.16 g), 18-crown-6 (236 mg) andacetonitrile (18 ml) was stirred for 15 min under an atmosphere ofargon. A mixture of methyl 3-(3-hydroxypropyl)phenoxyacetate (2.0 g) andtributylphosphine (1.99 g)in acetonitrile (10 ml) was added to thereaction mixture, followed by the dropwise addition of a solution ofcarbon tetrachloride (0.95 ml) in an acetonitrile (10 ml) with coolingin ice bath. The mixture was stirred overnight at room temperature. Themixture was diluted with ether and washed with aqueous 10% citric acid.After the addition of carbon tetrachloride (10 ml), the mixture waswashed with water and a saturated aqueous solution of sodium chloride,successively, dried over anhydrous magnesium sulfate, and evaporated.The reside was purified by silica gel column chromatography (ethylacetate:n-hexane=9:1) to give the title compound (1.47 g) having thefollowing physical data.

NMR: δ7.20 (1H, t, J=7Hz), 6.90-6.60 (3H, m), 4.60 (2H, s), 3.80 (3H,s), 2.74 (2H, t, J=7Hz), 2.30(2H, t, J=7 Hz), 1.98(2H, m).

Reference example 19 Methyl3-(4-amino-4-hydroxyiminobutyl)phenoxyacetate ##STR58##

To a mixture of ethanol-water (5:1) (30 ml) were added successively thecompound prepared in reference example 18 (1.01 g), hydroxyaminehydrochloride (331 mg) and sodium acetate (391 mg). The mixture wasrefluxed overnight. The mixture was concentrated under reduced pressure,and the residue was purified by silica gel column chromatography(n-hexane:ethyl acetate=1:1) to give the title compound (150 mg) havingthe following physical data.

NMR: δ7.13 (1H, t, J=7 Hz), 6.90-6.50 (3H, m), 5.10 (3H, brs), 4.60 (2H,s), 3.80 (3H, s), 2.63 (2H, t, J=7 Hz), 2.37 (2H, t, J=7 Hz), 1.95 (2H,m).

Reference example 20 Methyl3-(4-amino-4-diphenylmethylcarbonyloxyiminobutyl)phenoxy acetate##STR59##

A suspension of diphenylacetic acid (252 mg) and thionyl chloride (5.0ml) was refluxed for 1 h. The mixture was cooled to room temperature andconcentrated under reduced pressure. To a solution of the residue andthe compound prepared in reference example 19 (144 mg) in methylenechloride (5.0 ml) was added triethylamine (0.33 ml) at room temperature.The mixture was stirred overnight at room temperature quenched byaddition of water, and extracted with ether. The extract was washed withwater and a saturated aqueous solution of sodium chloride, successively,dried over anhydrous magnesium sulfate and evaporated. The residue waspurified by silica gel flash chromatography (n-hexane:ethyl acetate=1:1)to give the title compound (61 mg) having the following physical data.

NMR: δ7.40-7.00 (11H, m), 6.90-6.50 (3H, m), 5.10 (1H, s), 4.58 (2H, s),3.79 (3H, s), 2.60 (2H, m), 2.21 (2H, m), 1.90 (2H, m);

MS (m/z): 461 (M⁺ +1).

Reference example 21 1 -(5,5-Dibromo-4-pentenyl)-3-methoxybenzene##STR60##

To a solution of carbon tetrabromide (16.7 g)in methylene chloride (35ml) was added triphenyiphosphine (26.0 g) in methylene chloride (35 ml)at 0° C. and the mixture was stirred for 10 min. To the mixture wasadded a solution of 1-(3-formylpropyl)-3-methoxybenzene (3.00 g) inmethylene chloride (20 ml) at 0° C. The mixture was stirred for 30 minat 0° C. To the mixture was added gradually n-hexane and the mixture wasfiltered to remove triphenylphosphineoxide. The filtrate was washed withwater and a saturated aqueous solution of sodium chloride, successively,dried over anhydrous magnesium sulfate and evaporated. The residue waspurified by silica gel column chromatography (n-hexane:ethylacetate=24:1) to give the title compound (5.33 g) having the followingphysical data.

MS (m/z): 334 (M⁺).

TLC: Rf 0.34 (n-hexane:ethyl acetate=24:1).

Reference example 22 1-(4-pentynyl)-3-methoxybenzene ##STR61##

To a solution of the compound prepared in reference example 21 (3.58 g)in THF (40 ml) was added dropwise n-butyllithium (14.7 ml; 1.6M/L inhexane solution) at -70° C. The mixture was stirred for 30 min at -70°C. After quenched by addition of water and aqueous solution of ammoniumchloride at the same temperature, the mixture was warmed up to roomtemperature. The mixture was extracted with n-hexane - ethyl acetate(6:1). The extract was washed with water and a saturated aqueoussolution of sodium chloride, successively dried over anhydrous magnesiumsulfate, and evaporated. The residue was purified by silica gel columnchromatography (n-hexane:ethyl acetate=24:1) to give the title compound(1.86 g) having the following physical data.

TLC: Rf 0.32 (n-hexane:ethyl acetate=24:1);

IR(cm-⁻¹): ν3295, 2943, 2117, 1602, 1489, 1261.

Reference example 23 1-(7,7-Diphenyl-6-oxo-4-heptynyl)-3-methoxybenzene##STR62##

To a mixture of ethylmagnesium bromide (3.4 ml; 3.0 M/L in ethersolution) and THF (20 ml) was added dropwise a solution of the compoundprepared in reference example 22 (1.5 g) in THF (15 ml) over a 10 minperiod. The mixture was stirred for 2 h at room temperature. To themixture was added a solution of diphenylacetaldehyde (1.7 g) in THF (10ml). The mixture was stirred for 2 h. After quenched by addition ofammonium chloride, the mixture was extracted with ether. The extract waswashed with water and a saturated aqueous solution of sodium chloride,successively, dried over anhydrous magnesium sulfate and evaporated. Toa solution of the residue in ether (40 ml) was added manganese (IV)oxide (2.0 g) at room temperature. The mixture was stirred for 2 h. Themixture was filtrated and evaporated. The residue was purified by silicagel column chromatography (n-hexane:ethyl acetate=7:1) to give the titlecompound (1.99 g) having the following physical data.

MS (m/z): 368 (M⁺).

TLC: Rf 0.46 (n-hexane:ethyl acetate=3:1).

Reference example 241-(6-Imino-4-hydroxy-7,7-diphenyl-4-heptynyl)-3-methoxybenzene ##STR63##

A mixture of the compound (400 mg) prepared by the same procedure asreference example 14 using the compound prepared in reference example23, Raney nickel (300 mg; registered trade mark) and ethanol (5 ml) wasstirred overnight under an atmosphere of hydrogen. The mixture wasfiltered through Celite (registered trade mark) and evaporated. Theresidue was purified by silica gel column chromatography (ethylacetate:benzene=7:93) to give the title compound (184 mg) having thefollowing physical data.

MS (m/z): 385 (M⁺).

TLC: Rf 0.26 (n-hexane:ethyl acetate=3:1).

Reference example 251-[3-(3-Diphenylmethylisothiazol-5-yl)propyl]-3-methoxybenzene ##STR64##

A mixture of the compound prepared in reference example 24 (121 mg),p-chloranil (77 mg), phosphorus pentasulfide (209 mg) and toluene (2 ml)was refluxed for 30 min. After cooled to room temperature, to themixture was added benzene. The mixture was filtrated and evaporated. Theresidue was purified by silica gel column chromatography (n-hexane:ethylacetate=6:1) to give the title compound (62 mg) having the followingphysical data.

MS (m/z): 399 (M⁺).

TLC: Rf 0.30 (n-hexane:ethyl acetate=6:1).

EXAMPLE 1 Methyl 3-(4-diphenylmethyloxyiminobutyl)phenoxyacetate##STR65##

To a solution of the compound prepared in reference example 1 (300 mg)in ethanol (10 ml) was added diphenylmethyloxyamine (253 mg) at roomtemperature. The mixture was stirred overnight at room temperature andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (benzene:ethyl acetate=9:1) to give the titlecompound (520 mg) having the following physical data.

TLC: Rf 0.31 (n-hexane:ethyl acetate=4:1);

NMR: δ7.60-7.10 (12H, m), 6.90-6.80 (3H, m), 6.22 (1H, s), 4.60 (2H, s),3.79 (3H, s), 2.8-2.00 (4H, m), 1.80 (2H, m).

EXAMPLE 2 3-(4-Diphenylmethyloxyiminobutyl)phenoxyacetic acid ##STR66##

To a solution of the compound prepared in example 1 (305 mg) in amixture of dimethoxymethane (3.0 ml) and methanol (1.0 ml) was added 2Naqueous solution of sodium hydroxide (0.5 ml) at room temperature. Afterbeing stirred for 1 h, the mixture was quenched by addition of 1Nhydrochloric acid (0.5 ml) and extracted with ethyl acetate. The extractwas washed with water and a saturated aqueous solution of sodiumchloride, successively, dried over anhydrous magnesium sulfate andevaporated. The residue was purified by silica gel column chromatography(ethyl acetate:n-hexane=1:1) to give the title compound (277 mg) havingthe following physical data.

MS (m/z): 403 (M⁺), 381, 359, 345, 236, 219, 184, 168;

NMR: δ7.55 (1H, t, J=6 Hz), 7.40-7.10 (11H, m), 6.90-6.80 (3H, m), 6.20(1H, s), 4.62 (2H, s), 2.80-2.40 (3H, m), 2.17 (1H, brs), 1.80 (2H, m).

EXAMPLE 2(a)-2(c)

By the same procedure as in example 2, using the compound prepared inthe same procedure as in reference example 1→example 1 which was usingcorresponding phenoxyacetic acid derivative compound instead of methyl3-(4-hydroxybutyl) phenoxyacetate, compounds having the followingphysical data shown in the table 3 were given.

                                      TABLE 3                                     __________________________________________________________________________    EX.                                                                           No.                                                                              Structure of the example compound                                                                      MS (m/z)                                                                             IR.sub.(cm.spsb.-1.sub.)                   __________________________________________________________________________    2 (a)                                                                             ##STR67##               389(M.sup.+), 344, 222, 205,                                                         [KBr method] ν 3030, 2911, 1743,                                           1708, 1610, 1515, 1455, 1431, 1237,                                           1189, 1095, 1023, 919, 832, 746, 705       2 (b)                                                                             ##STR68##               403(M.sup.+), 360, 345, 236, 219, 184, 118,                                   152    ν 3030, 2927, 1736, 1611, 1586,                                            1510, 1454, 1301, 1218, 1180, 1081,                                           1022, 920, 830, 740, 702, 609              2 (c)                                                                             ##STR69##               390(M.sup.+  + 1)                                                                    ν 3031, 2922, 1734, 1586, 1494,                                            1454, 1241, 1160, 1084, 1020, 919,                                            746, 700                                   __________________________________________________________________________

The example compounds shown in table 3 are named as follows:

2(a) 4-(3-Diphenylmethyloxyiminopropyl)phenoxyacetic acid,

2(b) 4-(4-Diphenylmethyloxyiminobutyl)phenoxyacetic acid,

2(c) 3-(3-Diphenylmethyloxyiminopropyl)phenoxyacetic acid.

EXAMPLE 3 Methyl 3-(4-diphenylmethyloxyiminoheptyl)phenoxyacetate##STR70##

By the same procedure as in example 1, using the compound prepared inreference example 3, the title compound having the following physicaldata was given.

TLC: Rf 0.35 (n-hexane:ethyl acetate=3:1);

IR (cm⁻¹): ν3062, 3030, 2958, 2872, 1763, 1741, 1586, 1494, 1452, 1377,1289, 1209, 1159, 1088, 1025, 937, 744, 700.

EXAMPLE 4 3-(4-Diphenylmethyloxyiminoheptyl)phenoxyacetic acid ##STR71##

By the same procedure as in example 2, using the compound prepared inexample 3, the title compound having the following physical data wasgiven.

TLC: Rf 0.20 (chloroform:methanol=4:1);

IR (cm⁻¹): ν3031, 2961, 2872, 1737, 1587, 1494, 1454, 1375, 1241, 1160,1086, 1042, 938, 763, 744, 700.

EXAMPLE 5 Methyl 3-(4-diphenylmethyloxyaminoheptyl)phenoxyacetate##STR72##

To a solution of the compound prepared in example 3 (150 mg) in methanol(1 ml) was added sodium cyanoborohydride (82 mg) at room temperature.This solution was adjusted to pH 3 by addition of saturatedhydrochloride in methanol and the mixture was stirred for 2 h at roomtemperature. After being neutralized by addition of a saturated aqueoussolution of sodium bicarbonate, the mixture was extracted with ethylacetate. The extract was washed with water and aqueous solution ofsodium chloride, successively, dried over anhydrous magnesium sulfateand evaporated. The residue was purified by silica gel columnchromatography (n-hexane:ethyl acetate=3:1) to give title compound (147mg) having the following physical data.

TLC: Rf 0.34 (n-hexane:ethyl acetate=3:1);

IR (cm⁻¹): ν3030, 2932, 2869, 1764, 1741, 1586, 1493, 1452, 1376, 1209,1159, 1086, 1029, 888, 761, 743, 699.

EXAMPLE 6 3-(4-Diphenylmethyloxyaminoheptyl)phenoxyacetic acid ##STR73##

By the same procedure as example 2, using the compound prepared inexample 5 (125 mg), the title compound (115 mg) having the followingphysical data was given.

TLC: Rf 0.21 (chloroform:methanol=4:1);

IR (cm⁻¹): ν3031, 2932, 2871, 1738, 1586. 1494, 1454, 1374, 1241, 1159,1082, 1046, 915, 762, 744, 698.

EXAMPLE 7 Methyl 3-(3,3-diphenylmethylpropyl)aminocarbonylmethyl)phenoxyacetate ##STR74##

A mixture of 3-methoxycarbonylmethoxyphenylacetic acid (150 mg),2-chloro-N-methylpyridinium iodide (241 mg), 3,3-diphenylpropylamine(146 mg) and triethylamine (0.26 ml) in methylene chloride (7 ml) wasstirred overnight at room temperature. The mixture was poured into 1Nhydrochloric acid and extracted with ether. The extract was washed withwater and a saturated aqueous solution of sodium chloride, successively,dried over anhydrous magnesium sulfate and evaporated. The residue waspurified by silica gel column chromatography (ethyl acetate:methylenechloride=1:25) to give title compound (125 mg) having the followingphysical data.

TLC: Rf 0.33 (ethyl acetate:methylene chloride=1:9);

NMR: δ7.40-7.00 (11H, m), 6.90-6.70 (3H, m), 5.30 (1H, m), 4.63 (2H, s),3.83 (1H, t, J=7Hz), 3.80 (3H, s), 3.47 (2H, s), 3.17 (2H, dt, J=8,7Hz), 2.20 (2H, dt, J=5, 7Hz).

EXAMPLE 8 3-(3,3-diphenylpropyl)aminocarbonylmethyl)phenoxyacetic acid##STR75##

By the same procedure as example 2, using the compound prepared inexample 7 (119 mg), the title compound (98 mg) having the followingphysical data was given.

TLC: Rf 0.48 (methylene chloride:methanol=10:3);

IR (cm⁻¹): ν3295, 3024, 2880, 2526, 1757, 1584, 1557, 1490, 1469, 1450,1381, 1356, 1304, 1285, 1242, 1204, 1155, 1087, 1030, 958, 905, 880,776, 753, 741, 697, 674, 638, 614, 588, 557, 482, 456, 431.

EXAMPLE 8(a)-8(cc)

By the same procedure as in example 7→example 2, using correspondingphenoxyacetic acid derivative compounds and corresponding amines,compounds having the following physical data shown in the table 4 weregiven.

                                      TABLE 4                                     __________________________________________________________________________    EX.                                                                           No. Structure of the example compound                                                                            TLC    IR (cm.sup.-1)                      __________________________________________________________________________    8 (a)                                                                              ##STR76##                     Rf 0.50 (methylene chloride: methanol                                         = 10:3)                                                                              ν 3033, 1742, 1614, 1587,                                                  1495, 1438, 1213, 1159, 1082,                                                 1017, 780, 732, 702                 8 (b)                                                                              ##STR77##                     Rf 0.53 (methylene chloride: methanol                                         = 10:3)                                                                              ν 3436, 3031, 1742, 1603,                                                  1494, 1452, 1363, 1221, 1160,                                                 1083, 1029, 954, 775, 736, 700      8 (c)                                                                              ##STR78##                      Rf 0.30 (methylene chloride: methanol                                        = 10:3)                                                                              [KBr method] ν 3268, 3057,                                                 1724, 1636, 1588, 1561, 1492,                                                 1453, 1432, 1400, 1368, 1348,                                                 1314, 1283, 1259, 1231, 1172,                                                 1158, 1093, 1080, 1026, 951,                                                  919, 855, 787, 766, 744, 696,                                                 618, 605, 557, 532, 489             8 (d)                                                                              ##STR79##                     Rf 0.40 (methylene chloride: methanol                                         = 10:3)                                                                              [KBr method] ν 3297, 3058,                                                 2917, 1719, 1703, 1653, 1613,                                                 1589, 1531, 1494, 1451, 1434,                                                 1412, 1359, 1341, 1277, 1237,                                                 1161, 1085, 1032, 978, 752,                                                   742, 702, 642, 620                  8 (e)                                                                              ##STR80##                     Rf 0.40 (methylene chloride: methanol                                         = 10:3)                                                                              [KBr method] ν 3273, 3038,                                                 2916, 1753, 1674, 1590, 1516,                                                 1494, 1460, 1431, 1315, 1276,                                                 1241, 1163, 1098, 1085, 1030,                                                 965, 877, 784, 752, 693, 626,                                                 546, 507                            8 (f)                                                                              ##STR81##                     Rf 0.40 (methylene chloride: methanol                                         = 10:3)                                                                              [KBr method] ν 3318, 3063,                                                 2921, 1752, 1646, 1586, 1540,                                                 1495, 1440, 1255, 1165, 1100,                                                 1028, 966, 914, 877, 760, 701,                                                541                                 8 (g)                                                                              ##STR82##                     Rf 0.40 (methylene chloride: methanol                                         = 10:3)                                                                              [KBr method] ν 3309, 3028,                                                 2912, 1724, 1625, 1604, 1580,                                                 1494, 1435, 1299, 1246, 1160,                                                 1087, 1013, 924, 886, 774, 756,                                               742, 704, 633, 585, 542             8 (h)                                                                              ##STR83##                     Rf 0.38 (methylene chloride: methanol                                         = 10:3)                                                                              [KBr method] ν 3233, 3032,                                                 2912, 1719, 1641, 1609, 1588,                                                 1532, 1494, 1458, 1436, 1341,                                                 1300, 1250, 1161, 1098, 1086,                                                 1054, 985, 914, 888, 813, 764,                                                748, 698, 602, 574, 531             8 (i)                                                                              ##STR84##                     Rf 0.40 (methylene chloride: methanol                                         = 10:3)                                                                              [KBr method] ν 3314, 3057,                                                 1737, 1639, 1587, 1511, 1490,                                                 1446, 1367, 1324, 1304, 1221,                                                 1158, 1075, 1028, 1000, 972,                                                  918, 879, 774, 695, 651, 628,                                                 549, 452                            8 (j)                                                                              ##STR85##                     Rf 0.50 (methylene chloride: methanol                                         = 10:3)                                                                              ν 3351, 3027, 2933, 1734,                                                  1713, 1603, 1558, 1494, 1452,                                                 1364, 1227, 1160, 1089, 1031,                                                 914, 776, 752, 701                  8 (k)                                                                              ##STR86##                     Rf 0.53 (methylene chloride: methanol                                         = 10:3)                                                                              ν 3033, 2930, 1742, 1611,                                                  1586, 1495, 1453, 1413, 1357,                                                 1267, 1208, 1158, 1079, 1017,                                                 878, 777, 700                       8 (l)                                                                              ##STR87##                     Rf 0.53 (methylene chloride: methanol                                         = 10:3)                                                                              ν 3031, 2927, 1746, 1604,                                                  1495, 1452, 1361, 1223, 1160,                                                 1083, 1029, 953, 879, 783, 735,                                               699                                 8 (m)                                                                              ##STR88##                     Rf 0.33 (methylene chloride: methanol                                         = 10:3)                                                                              [KBr method] ν 3320, 3031,                                                 2952, 2587, 1737, 1641, 1611,                                                 1580, 1541, 1485, 1461, 1423,                                                 1377, 1349, 1297, 1279, 1239,                                                 1165, 1103, 1030, 1009, 925,                                                  877, 781, 770, 735, 695             8 (n)                                                                              ##STR89##                     Rf 0.50 (methylene chloride: methanol                                         = 10:3)                                                                              [KBr method] ν 3320, 3034,                                                 2948, 1750, 1644, 1586, 1532,                                                 1495, 1459, 1426, 1377, 1304,                                                 1258, 1243, 1212, 1164, 1100,                                                 1032, 935, 873, 756, 698, 644,                                                605                                 8 (o)                                                                              ##STR90##                     Rf 0.56 (methylene chloride: methanol                                         = 10:3)                                                                              [KBr method] ν 3279, 3027,                                                 2932, 2587, 1744, 1669, 1591,                                                 1518, 1495, 1430, 1383, 1329,                                                 1256, 1206, 1174, 1094, 1031,                                                 939, 923, 853, 782, 746, 698,                                                 631, 559                            8 (p)                                                                              ##STR91##                     Rf 0.45 (methylene chloride: methanol                                         = 10:3)                                                                              [KBr method] ν 3344, 3031,                                                 2944, 1746, 1640, 1603, 1523,                                                 1495, 1454, 1419, 1244, 1168,                                                 1090, 1031, 902, 785, 781, 702,                                               642, 584, 538                       8 (q)                                                                              ##STR92##                     Rf 0.47 (methylene chloride: methanol                                         = 10:3)                                                                              [KBr method] ν 3347, 2938,                                                 2866, 2549, 1737, 1615, 1587,                                                 1553, 1493, 1452, 1437, 1362,                                                 1293, 1226, 1158, 1083, 1028,                                                 908, 877, 790, 758, 704, 630,                                                 587, 543                            8 (r)                                                                              ##STR93##                     Rf 0.44 (methylene chloride: methanol                                         = 10:3)                                                                              [KBr method] ν 3205, 2930,                                                 1736, 1655, 1586, 1494, 1452,                                                 1229, 1160, 1082, 1023, 875,                                                  762, 746, 698                       8 (s)                                                                              ##STR94##                     Rf 0.50 (methylene chloride: methanol                                         = 10:3)                                                                              [KBr method] ν 3482, 3159,                                                 3053, 2965, 2905, 2759, 2524,                                                 1746, 1637, 1584, 1489, 1457,                                                 1432, 1397, 1359, 1322, 1309,                                                 1272, 1229, 1156, 1087, 1028,                                                 956, 927, 873, 774, 741, 695,                                                 637, 600, 523, 463, 431             8 (t)                                                                              ##STR95##                     Rf 0.32 (methylene chloride: methanol                                         = 10:3)                                                                              [KBr method] ν 3326, 3023,                                                 2920, 2880, 1719, 1585, 1494,                                                 1484, 1451, 1435, 1378, 1312,                                                 1293, 1249, 1208, 1168, 1091,                                                 894, 865, 785, 770, 750, 696,                                                 606, 585, 495, 468                  8 (u)                                                                              ##STR96##                     Rf 0.49 (methylene chloride: methanol                                         = 10:3)                                                                              ν 3031, 2931, 1746, 1613,                                                  1587, 1495, 1454, 1416, 1266,                                                 1211, 1159, 1082, 1018, 883,                                                  778, 756, 700                       8 (v)                                                                              ##STR97##                     Rf 0.53 (methylene chloride: methanol                                         = 10:3)                                                                              ν 3030, 2927, 1746, 1603,                                                  1494, 1452, 1361, 1217, 1161,                                                 1082, 1029, 1002, 956, 883,                                                   752, 699                            8 (w)                                                                              ##STR98##                     Rf 0.21 (methylene chloride: methanol                                         = 10:3)                                                                              [KBr method] ν 3347, 3293,                                                 3033, 2935, 1742, 1712, 1640,                                                 1610, 1587, 1547, 1492, 1454,                                                 1432, 1350, 1301, 1281, 1213,                                                 1159, 1104, 1080, 1020, 922,                                                  887, 781, 749, 695, 498, 456        8 (x)                                                                              ##STR99##                     Rf 0.43 (methylene chloride: methanol                                         = 10:3)                                                                              [KBr method] ν 3326, 3061,                                                 1752, 1651, 1614, 1585, 1535,                                                 1496, 1455, 1427, 1381, 1299,                                                 1246, 1220, 1166, 1106, 980,                                                  922, 874, 789, 769, 745, 697,                                                 640, 532                            8 (y)                                                                              ##STR100##                    Rf 0.40 (methylene chloride: methanol                                         = 10:3)                                                                              [KBr method] ν 3279, 1737,                                                 1704, 1673, 1589, 1523, 1496,                                                 1453, 1414, 1301, 1280, 1234,                                                 1160, 1086, 921, 771, 747, 693,                                               630, 507                            8 (z)                                                                              ##STR101##                    Rf 0.38 (methylene chloride: methanol                                         = 10:3)                                                                              [KBr method] ν 3328, 3063,                                                 3030, 2916, 2582, 1752, 1641,                                                 1595, 1537, 1495, 1455, 1432,                                                 1319, 1300, 1251, 1175, 1094,                                                 1030, 913, 847, 790, 759, 699,                                                644, 539, 508                       8 (aa)                                                                             ##STR102##                    Rf 0.50 (methylene chloride: methanol                                         = 10:3)                                                                              [KBr method] ν 3339, 3060,                                                 2931, 1737, 1603, 1561, 1494,                                                 1452, 1224, 1159, 1087, 1032,                                                 1008, 881, 783, 755, 742, 701,                                                586, 540                            8 (bb)                                                                             ##STR103##                    Rf 0.33 (methylene chloride: methanol                                         = 10:3)                                                                              [KBr method] ν 3209, 3032,                                                 1736, 1656, 1494, 1452, 1229,                                                 1161, 1084, 1002, 876, 762,                                                   746, 699                            8 (cc)                                                                             ##STR104##                    RF 0.48 (methylene chloride: methanol                                         = 10:3)                                                                              [KBr method] ν 3181, 3070,                                                 3025, 2924, 2524, 1736, 1631,                                                 1584, 1490, 1460, 1440, 1397,                                                 1335, 1313, 1284, 1265, 1232,                                                 1159, 1113, 1094, 1030, 958,                                                  929, 912, 881, 783, 772, 736,                                                 691, 637, 612, 597, 545, 470,                                                 443                                 __________________________________________________________________________

The example compounds shown in table 4 are named as follows:

8(a) 3-(N-Benzyl-N-phenylaminocarbonylmethyl)phenoxyacetic acid,

8(b) 3-(N,N-Dibenzylaminocarbonylmethyl)phenoxyacetic acid,

8(c) 3-(N-Benzylaminocarbonylmethyl)phenoxyacetic acid,

8(d) 3-(Diphenylmethylaminocarbonylmethyl)phenoxyacetic acid,

8(e) 3-[(N,N-Diphenylamino )aminocarbonylmethyl]phenoxyacetic acid.

8(f) 3-[(1,2-Diphenylethylaminocarbonylmethyl)phenoxyacetic acid,

8(g) 3-(2,2-Diphenylethylaminocarbonylmethyl)phenoxyacetic acid,

8(h) 3-(Diphenylmethyloxyaminocarbonylmethyl)phenoxyacetic acid,

8(i) 3-[(1,1-Diphenylmethylideneamino)aminocarbonylmethyl]phenoxyaceticacid,

8(j) 3-[3-(3,3-Diphenylpropylaminocarbonyl)propyl]phenoxyacetic acid,

8(k) 3-[3-(N-Benzyl-N-phenylaminocarbonyl)propyl]phenoxyacetic acid,

8(l) 3-[3-(N,N-Dibenzylaminocarbonyl)propyl]phenoxyacetic acid,

8(m) 3-(3-Benzylaminocarbonylpropyl)phenoxyacetic acid,

8(n) 3-(3-Diphenylmethylaminocarbonylpropyl)phenoxyacetic acid,

8(o) 3-[3-[(N,N-Diphenylamino)aminocarbonyl]propyl]phenoxyacetic acid,

8(p) 3-[3-(1,2-Diphenylethylaminocarbonyl)propyl]phenoxyacetic acid,

8(q) 3-[3-(2,2-Diphenylethylaminocarbonyl)propyl]phenoxyacetic acid,

8(r) 3-(3-Diphenylmethyloxyaminocarbonylpropyl)phenoxyacetic acid,

8(s) 3-[3-[(1,1-Diphenylmethylideneamino)aminocarbonyl]propyl]phenoxyacetic acid,

8(t) 3-[2-(3,3-Diphenylpropylaminocarbonyl)ethyl]phenoxyacetic acid,

8(u) 3-[2-(N-Benzyl-N-phenylaminocarbonyl)ethyl]phenoxyacetic acid,

8(v) 3-[2-(N,N-Dibenzylaminocarbonyl)ethyl]phenoxyacetic acid,

8(w) 3-(2-Benzylaminocarbonylethyl)phenoxyacetic acid,

8(x) 3-(2-Diphenylmethylaminocarbonylethyl)phenoxyacetic acid,

8(y) 3-[2-[(N,N-Diphenylamino)aminocarbonyl]ethyl]phenoxyacetic acid.

8(z) 3-[2-(1,2-Diphenylethylaminocarbonyl)ethyl]phenoxyacetic acid,

8(aa) 3-[2-(2,2-Diphenylethylaminocarbonyl)ethyl]phenoxyacetic acid,

8(bb) 3-(2-Diphenylmethyloxyaminocarbonylethyl)phenoxyacetic acid and

8(cc) 3-[2-[(1,1-Diphenylmethylideneamino)aminocarbonyl]ethyl]phenoxyacetic acid.

EXAMPLE 9 3-(4-Diphenylaminosulfonyl-3-butenyl)phenoxyacetic acid##STR105##

To a solution of the compound (0.08 g) prepared by the same procedure asin reference example 1, using the compound prepared in reference example8, in acetone (2.0 ml) was added 8N Jone's reagent (0.1 ml) at 0° C.After stirring for 10 min at 0° C., to the mixture was added isopropylalcohol (0.5 ml). The mixture was stirred for 10 min, water was addedand the mixture was extracted with ether. The extract was washed withwater and a saturated aqueous solution of sodium chloride, successively,dried over anhydrous magnesium sulfate and evaporated. The residue waspurified by silica gel column chromatography (methylenechloride→methylene chloride:methanol=40:1) to give the title compound(0.035 g) having the following physical data.

TLC: Rf 0.18 (methylene chloride:methanol=5:1);

IR [KBr tablet method] (cm⁻¹): ν3435, 3051, 2928, 1749, 1714, 1611,1586, 1489, 1452, 1424, 1353, 1262, 1224, 1193, 1164, 1147, 1091, 1027,1011, 975, 912, 865, 824, 781, 757, 694, 631, 596, 547.

EXAMPLE 10 3-(4-Diphenylaminosulfonylbutyl)phenoxyacetic acid ##STR106##

To a solution of the compound prepared in example 9 (410 mg) in ethylacetate (5.0 ml) was added an excess amount of diazomethane in ether at0° C. After 10 min, the mixture was evaporated. The residue was purifiedby silica gel column chromatography (n-hexane:ethyl acetate=2:1) to givea methyl ester compound (56 mg). To a solution of the methyl estercompound (56 mg) in methanol (5 ml) was added 10% palladium on activatedcarbon (50 mg) at room temperature. The mixture was stirred vigorouslyfor 6 h under an atmosphere of hydrogen. The catalyst was removed byfiltration through Celite. Evaporation of the solvent gave (54 mg) ofthe residue. By the same procedure as in example 2, using the residue,the title compound (36 mg) having physical data was given.

TLC: Rf 0.21 (methylene chloride:methanol=5:1);

IR [KBr tablet method] (cm⁻¹): ν2925, 2862, 2590, 1750, 1710, 1612,1586, 1488, 1463, 1451, 1424, 1350, 1302, 1287, 1258, 1243, 1218, 1197,1164, 1146, 1103, 1078, 1027, 1012, 978, 913, 865, 780, 759, 708, 695,626, 594, 534.

EXAMPLE 11 Methyl 3-(4-diphenylmethyloxybutyl)phenoxyacetate ##STR107##

To a solution of methyl 3-(4-hydroxybutyl)phenoxyacetate (372 mg) anddiphenylmethyltrichloroacetoimidate (771 mg) in chloroform (4 ml) andcyclohexane (8 ml) was added a catalytic amount of boron trifluorideetherate at 0° C. After being stirred for 30 min at 0° C., the mixturewas quenched by addition of a saturated aqueous solution of sodiumbicarbonate and extracted with ether. The extract was washed with waterand a saturated aqueous solution of sodium chloride, successively, driedover anhydrous magnesium sulfate and evaporated. The residue waspurified by silica gel column chromatography (n-hexane:ethylacetate=4:1) to give the title compound (343 mg) having the followingphysical data.

NMR: δ7.50-7.00 (11H, m), 6,90-6.50 (3H, m), 5.27 (1H, s), 4.58 (2H, s),3.77 (3H, s), 3.43 (2H, t, J=7Hz), 2.58 (2H, t, J=7Hz), 1.68 (4H, m);

IR (cm⁻¹): ν3029, 2938, 2860, 1762, 1586, 1494, 1453, 1211, 1159, 1095,1029, 743,699.

EXAMPLE 12 3-(4-Diphenylmethyloxybutyl)phenoxyacetic acid ##STR108##

By the same procedure as in example 2, using the compound prepared inexample 11 (340 mg), the title compound (277 mg) having the followingphysical data was given.

TLC: Rf 0.18 (chloroform:methanol=9:1);

IR (cm⁻¹): ν3030, 2938, 2862, 1733, 1586, 1494, 1454, 1242, 1160, 1094,761, 744, 699.

EXAMPLE 12(a) 3-(3-Diphenylmethyloxypropyl)phenoxyacetic acid ##STR109##

By the same procedure as in example 11→example 2, using methyl3-(3-hydroxypropyl)phenoxyacetate instead of methyl 3-(4-hydroxybutyl)phenoxycacetate, the title compound having the following physical datawas given.

mp.: 110°-112° C.;

TLC: Rf 0.15 (ethyl acetate);

IR [KBr tablet method] (cm⁻¹): ν2861, 1748, 1710, 1594, 1494, 1431,1398, 1307, 1237, 1174, 1105, 1083, 1059, 1030, 904, 859, 783, 741, 697,651, 612.

EXAMPLE 13 Methyl 3-(4-triphenylmethoxybutyl)phenoxyacetate ##STR110##

To a solution of methyl 3-(4-hydroxybutyl) phenoxyacetate (174 mg) indimethylformamide (8.0 ml) was added successively trityl chloride (223mg) and N,N-dimethylaminopyridine (88 mg). After stirred overnight atroom temperature, the mixture was quenched by addition of water andextracted with ether. The extract was washed with water and a saturatedaqueous solution of sodium chloride, successively, dried over anhydrousmagnesium sulfate and evaporated. The residue was purified by flashsilica gel chromatography (n-hexane:ethyl acetate=4:1) to give the titlecompound (228 mg) having the following physical data.

NMR: δ7.50-7.00 (16H, m), 6.90-6.50 (3H, m), 4.58 (2H, s), 3.78 (3H, s),3.04 (2H, t, J=7Hz), 2.53 (2H, m), 1.66 (4H, m);

IR (cm⁻¹): ν3057, 2938, 2865, 1764, 1741, 1586, 1490, 1449, 1289, 1211,1158, 1075, 1033, 764, 707.

EXAMPLE 14 3-(4-Triphenylmethoxybutyl)phenoxyacetic acid ##STR111##

By the same procedure as in example 2, using the compound prepared inexample 13 (220 mg), the title compound (159 mg) having the followingphysical data was given.

TLC: Rf 0.13 (chloroform:methanol=9:1);

IR (cm⁻¹): ν3058, 2937, 2866, 1738, 1586, 1490, 1449, 1240, 1159, 1075,900, 764, 698.

EXAMPLE 15 Methyl 3-(3-diphenylmethyloxycarbonylpropyl)phenoxyacetate##STR112##

A mixture of 3-(3-methoxycarbonylmethoxyphenyl)propionic acid (195 mg),2-chloro-N-methylpyridinium iodide (297 mg), diphenylmethanol (185 mg),triethylamine (0.32 ml), and catalytic amount ofN,N-dimethyaminopyridine in methylene chloride (6 ml) was stirredovernight at room temperature. The mixture was poured into 1Nhydrochloric acid extracted with ethyl acetate. The extract was washedwith water and saturated aqueous solution of sodium chloride,successively, dried over anhydrous magnesium sulfate and evaporated. Theresidue was purified by silica gel column chromatography (n-hexane:ethylacetate=4:1) to give the title compound (128 mg) having the followingphysical data.

TLC: Rf 0.54 (n-hexane:ethyl acetate=7:3);

NMR: δ7.40-7.10 (11H, m), 6.89 (1H, s), 6.85-6.60 (3H, m), 4.60 (2H, s),3.79 (3H, s), 2.60 (2H, t, J=6 Hz), 2.43 (2H, t, J=7 Hz), 1.97 (2H, m).

EXAMPLE 16 Methyl3-[3-(4-diphenylmethylpyrazol-1-yl)propyl]phenoxyacetate ##STR113##

To a suspension of sodium hydride (217 mg, 60% dispersion) indimethylformamide (10 ml) was added dropwise a solution of4-diphenylmethylpyrazole (1.27 g) in dimethylformamide (50 ml) at roomtemperature. After being stirred for 30 min at room temperature, to themixture was added dropwise a solution of the compound prepared inreference example 9(1.56 g) in dimethylformamide. After being stirredfor 1 h, the mixture was quenched by addition of 1N hydrochloric acidand extracted with a mixture of ethyl acetate-n-hexane (1:2). Theextract was washed with saturated aqueous solution of sodium chloride,dried over anhydrous magnesium sulfate and evaporated. The residue waspurified by silica gel column chromatography (ethylacetate:n-hexane=3:7) to give the title compound (2.01 g) having thefollowing physical data.

TLC: Rf 0.59 (n-hexane:ethyl acetate=1:1);

NMR: δ7.40-7.10 (12H, m), 6.93 (1H, s), 6.80-6.60 (3H, m), 5.35 (1H, s),4.58 (2H, s), 4.03 (2H, t, J=7Hz), 3.79 (3H, s), 2.56 (2H, t, J=7Hz),2.16(2 H, m).

EXAMPLE 17 3-[3-(4-diphenylmethylpyrazol-1-yl)propyl]phenoxyacetic acid##STR114##

By the same procedure as in example 2, using the compound prepared inexample 16 (1.5 g), the title compound (1.1 g) having the followingphysical data was given.

TLC: Rf 0.21 (chloroform:methanol=4:1);

IR [KBr tablet method] (cm⁻¹): ν3027, 2930, 1736, 1586, 1493, 1451,1219, 1159, 1079, 1014, 874, 753, 701, 507.

EXAMPLE 17(a)-17(dd)

By the same procedure as in reference example 9→example 16→example 17,using corresponding compounds, compounds having the following physicaldata shown in the table 5 were given.

                                      TABLE 5                                     __________________________________________________________________________    EX.                                                                           No. Structure of the example compound                                                                             TLC    IR.sub.(cm.spsb.-1.sub.)           __________________________________________________________________________    17(a)                                                                              ##STR115##                     Rf 0.26 (chloroform: methanol=                                                       ν 3027, 2936, 2861, 2517,                                                  1736, 1586, 1494, 1451, 1374,                                                 1219, 1158, 1079, 1015, 873,                                                  753, 700, 635, 508, 475            17(b)                                                                              ##STR116##                     Rf 0.19 (chloroform: methanol=                                                       ν 3029, 2932, 1737, 1587,                                                  1494, 1452, 1373, 1242, 1160,                                                 1080, 1032, 848, 780, 753,                                                    700                                17(c)                                                                              ##STR117##                     Rf 0.15 (chloroform: methanol=                                                       ν 3028, 2929, 1736, 1586,                                                  1494, 1452, 1216, 1160, 1079,                                                 878, 754, 699, 637                 17(d)                                                                              ##STR118##                     Rf 0.14 (chloroform: methanol=                                                       ν 3029, 2929, 2508, 1736,                                                  1586, 1493, 1454, 1222, 1160,                                                 1114, 1081, 1032, 848, 751,                                                   701, 639                           __________________________________________________________________________    EX.                                                                           No. Structure of the example compound                                                                             TLC (Rf)                                                                             NMR (δ)                      __________________________________________________________________________    17(e)                                                                              ##STR119##                     0.60  (methanol: methylene chloride=                                          1:4)   7.30-7.00(12H, m), 6.96(1H,                                                   s), 6.90-6.80(2H, m), 6.76(1H,                                                d), 5.30(1H, s), 4.60(2H, s),                                                 4.10(2H, t), 2.67(2H, t),                                                     1.83(2H, m), 1.60(2H, m).          17(f)                                                                              ##STR120##                     0.63 (methanol: methylene chloride=                                           1:4)   7.50(1H, brs), 7.35-7.00(13H,                                                 m), 6.93(1H, s), 6.90(1H, t),                                                 6.75(1H, d), 5.30(1H, s),                                                     4.60(2H, s), 4.05(2H, t),                                                     2.67(2H, t), 1.85(2H, m),                                                     1.63(2H, m), 1.30(2H, m).          17(g)                                                                              ##STR121##                     0.19 (methanol: methylene chloride=                                           1:5)   7.4-7.0(12H, m), 6.82(2H, m),                                                 6.72(1H, s), 6.67(1H, t),                                                     6.0-4.8(1H, brs), 5.28(1H, s),                                                .58(2H, s), 4.29(2H, t),                                                      3.05(2H, t)                        17(h)                                                                              ##STR122##                     0.33 (methanol: methylene chloride=                                           1:5)   8.0-7.2(1H, brs), 7.4-7.0(13H,                                                m), 7.02(1H, s), 6.92(1H, t),                                                 6.76(1H, d), 5.32(1H, s),                                                     4.58(2H, s), 4.08(2H, t),                                                     2.66(2H, t), 2.17(2H, tt)          17(i)                                                                              ##STR123##                     0.26 (chloroform: methanol= 4:1)                                                     7.95(1H, brs), 7.36-7.13(12H,                                                 m), 7.05(1H, s), 6.96(1H, d),                                                 6.92(1H, m), 6.78(1H, dd),                                                    6.48(1H, d), 6.29(1H, dt),                                                    5.33(1H, s), 4.82(2H, d),                                                     4.56(2H, s).                       17(j)                                                                              ##STR124##                     0.24 (methanol: methylene  chloride=                                          1:5)   (CDCl3CD3OD) 7.4-7.0(11H, m),                                                 6.94(2H, d), 6.80(2H, d),                                                     6.72(1H, s), 5.26(1H, s),                                                     4.56(2H, s), 4.20(2H, t),                                                     3.03(2H, t)                        17(k)                                                                              ##STR125##                     0.26 (methanol: methylene chloride=                                           1:5)   7.5-7.1(11H, m), 7.01(2H, d),                                                 6.95(1H, s), 6.82(2H, d),                                                     5.34(1H, s), 4.58(2H, s),                                                     4.07(2H, t), 2.49(2H, t),                                                     2.08(2H, tt)                       17(l)                                                                              ##STR126##                     0.28 (methanol: methylene chloride=                                           1:5)   7.5-7.1(11H, m), 7.02(2H, d),                                                 6.96(1H, s), 6.82(2H, d),                                                     6.6-5.6(1H, brs), 5.33(1H, s),                                                .59(2H, s), 4.07(2H, t),                                                      2.52(2H, t), 1.82(2H, m),                                                     1.51(2H, m).                       17(m)                                                                              ##STR127##                     0.17 (methanol: methylene chloride=                                           1:5)   7.4-7.3(12H, m), 7.05(1H, s),                                                 6.9-6.7(3H, m), 5.32(1H, s),                                                  5.20(2H, s), 4.58(2H, s).          17(n)                                                                              ##STR128##                     0.31 (chloroform: methanol= 4:1)                                                     8.70-8.00(3H,                                                                 m), 7.75-7.50(1H,                                                             m), 7.35-6.97(9H,                                                             m), 6.94-6.70(3H, m), 5.43(1H,                                                brs), 5.60(2H, brs), 4.08(2H,                                                 m), 2.72(2H, m), 2.06-1.50(4H,                                                m).                                17(o)                                                                              ##STR129##                     0.16 (methanol: methylene chloride=                                           1:5)   8.47(2H, m), 7.61(1H, d),                                                     7.40-7.13(8H, m), 7.09(1H, s),                                                .00-6.80(3H, m), 6.43(1H, d),                                                 6.27(1H, dt), 5.42(1H, s),                                                    4.87(2H, d), 4.62(2H, s).          17(p)                                                                              ##STR130##                     0.29 (chloroform: methanol= 4:1)                                                     7.36-7.13(11H, m), 6.95(1H,                                                   s), 6.94-6.70(4H, m), 5.33(1H,                                                s), 4.75(2H, s), 4.03(2H, t),                                                 3.84(3H, s), 2.50(2H, t),                                                     2.20-2.02(2H, m).                  17(q)                                                                              ##STR131##                     0.28 (methanol: methylene chloride=                                           1:5)   7.83(1H, d), 7.4-7.1(11H, m),                                                 7.07(1H, s), 7.00(1H, dd),                                                    6.97(1H, d), 6.6-5.8(1H, brs),                                                .43(2H, m), 5.35(1H, s),                                                      4.87(2H, m), 4.75(2H, s).          17(r)                                                                              ##STR132##                     0.22 (methanol: methylene chloride=                                           1:5)   8.02(1H, d), 7.40(1H, s),                                                     7.4-7.1(11H, m), 7.07(1H, d,),                                                .03(1H, d), 6.88(1H, dd),                                                     6.32(1H, dt), 6.2-5.2(1H,                                                     brs), 5.36(1H, s), 4.90(2H,                                                   d), 4.68(2H, s).                   17(s)                                                                              ##STR133##                     0.32 (chloroform: methanol= 4:1)                                                     7.38-6.98(14H, m), 6.75(1H,                                                   d), 6.65(1H, t), 6.17(1H, dt),                                                .44(1H, brs), 5.36(1H, s),                                                    4.88(2H, d), 4.57(2H, s),                                                     2.20(3H, s).                       17(t)                                                                              ##STR134##                     0.38 (chloroform: methanol= 4:1)                                                     7.38-7.00(13H,                                                                m), 7.00-6.60(1H, brs),                                                       6.86(1H, d), 6.74(1H, s),                                                     6.47(1H, d), 6.24(1H, dt),                                                    5.32(1H, s), 4.79(2H, d),                                                     4.62(2H, s), 2.24(3H, s).          17(u)                                                                              ##STR135##                     0.32 (chloroform: methanol= 4:1)                                                     7.38-7.00(12H,                                                                m), 7.00-6.20(1H, brs),                                                       6.78(1H, s), 6.70(1H, s),                                                     6.63(1H, s), 6.43(1H, d),                                                     6.26(1H, dt), 5.33(1H, s),                                                    4.81(2H, d), 4.56(2H, s),                                                     2.26(3H, s).                       17(v)                                                                              ##STR136##                     0.31 (chloroform: methanol= 4:1)                                                     7.40-6.90(14H, m), 6.74(1H,                                                   dd), 6.63(1H, d), 6.40(1H,                                                    brs), 6.20(1H, dt), 5.35(1H,                                                  s), 4.85(2H, d), 4.57(2H, s),                                                 2.20(3H, s).                       17(w)                                                                              ##STR137##                     0.40 (methanol: methylene chloride=                                           1:4)   8.63 and 8.47(1H, s), 8.56 and                                                8.53(1H, d), 7.78-7.73 and                                                    7.62-7.37(1H,                                                                 m), 7.45-7.22(6H,                                                             m), 7.16-7.09(1H,                                                             m), 6.79-6.65(3H, m), 4.43(2H,                                                s), 4.38-4.33(2H,                                                             m), 2.96-2.88(2H, m)               17(x)                                                                              ##STR138##                     0.49 (methanol: methylene chloride=                                           1:4)   8.71 and 8.62(1H, s), 8.61 and                                                8.55(1H, d), 7.80-7.76 and                                                    7.70-7.67(1H,                                                                 m), 7.50-7.25(6H, m),                                                         7.13-7.06(1H,                                                                 m), 6.75-6.65(3H, m), 4.45(2H,                                                s), 4.20-4.10(2H, m),                                                         2.60-2.50(2H,                                                                 m), 2.01-1.92(2H, m)               17(y)                                                                              ##STR139##                     0.46 (methanol: methylene chloride=                                           1:4)   8.81 and 8.67(1H, s), 8.57 and                                                8.52(1H, d), 7.73-7.65(1H, m),                                                .50-7.20(6H, m), 7.10-7.05(2H,                                                m), 6.85(1H, t), 6.73(1H, d),                                                 4.51 and 4.48(2H,                                                             s), 4.25-4.18(2H, m),                                                         2.75-2.65(2H,                                                                 m), 2.10-1.98(2H, m)               17(z)                                                                              ##STR140##                     0.46 (methanol: methylene chloride=                                           1:4)   8.71 and 8.62(1H, s), 8.55 and                                                8.52(1H, d), 7.78-7.74 and                                                    7.70-7.66(1H,                                                                 m), 7.47-7.15(6H, m),                                                         7.13-7.08(2H, m), 6.88(1H, t),                                                6.74(1H, d), 4.54(2H, s),                                                     4.25-4.18(2H, m),                                                             2.73-2.65(2H,                                                                 m), 1.80-1.60(4H, m).              17(aa)                                                                             ##STR141##                     0.43 (methanol: methylene chloride=                                           1:4)   8.72 and 8.64(1H,                                                             s), 8.59-8.50(1H,                                                             m), 7.78-7.73 and                                                             7.68-7.65(1H,                                                                 m), 7.46-7.15(6H,                                                             m), 7.14-7.07(2H,                                                             m), 6.90-6.85(1H, m),                                                         6.78-6.73 (1H, m), 4.52(2H,                                                   s), 4.18(2H, t), 2.67(2H, t),                                                 1.80-1.69(2H,                                                                 m), 1.69-1.56(2H, m),                                                         1.44-1.34(2H, m)                   17(bb)                                                                             ##STR142##                     0.22 (methanol: methylene chloride=                                           1:5)   8.80(0.4H, d), 8.70(0.6H, d),                                                 8.67(0.6H, dd), 8.62(0.4H,                                                    dd), 7.87-7.72(1H, m),                                                        7.60-6.90(9H,                                                                 m), 6.90-6.78(1H, m),                                                         6.63(0.4H, d), 6.55(0.6H, d),                                                 6.37(0.6H, dt), 6.30(0.4H,                                                    dt), 4.92-4.77(2H, m),                                                        4.67(0.8H, s), 4.65(1.2H, s).      17(cc)                                                                             ##STR143##                     0.19 (methanol: methylene chloride=                                           1:5)   7.4-7.0(12H, m), 6.8-6.0(5H,                                                  m), 5.32(1H, s), 4.58(2H, s),                                                 4.44(2H, t), 4.24(2H, t)           17(dd)                                                                             ##STR144##                     0.43 (methanol: methylene chloride=                                           1:4)   8.67 and 8.57(1H, s), 8.56 and                                                8.53(1H, d), 7.77-7.73 and                                                    7.70-7.65(1H,                                                                 m), 7.45-7.25(6H,                                                             m), 7.13-7.06(1H,                                                             m), 6.55-6.45(3H,                                                             m), 4.55-4.40(4H,                                                             m), 4.25-4.15 (2H,                 __________________________________________________________________________                                               m)                             

The example compounds shown in table 5 are named as follows:

17(a) 3-[4-(4-Diphenylmethylpyrazol-1-yl)butyl]phenoxyacetic acid,

17(b) 3-[3-(4-Diphenylmethyl-1,2,3-triazol-2-yl)propyl]phenoxyaceticacid,

17(c) 3-[3-(4-Diphenylmethyl-1,2,3-triazol-1-yl)propyl]phenoxyaceticacid,

17(d) 3-[3-(4-Diphenylmethyl-1,2,3-triazol-3-yl)propyl]phenoxyaceticacid,

17(e) 2-[4-(4-Diphenylmethylpyrazol-1-yl)butyl]phenoxyacetic acid,

17(f) 2-[5-(4-Diphenylmethylpyrazol-1-yl)pentyl]phenoxyacetic acid,

17(g) 3-[2-(4-Diphenylmethylpyrazol-1-yl)ethyl]phenoxyacetic acid,

17(h) 2-[3-(4-Diphenylmethylpyrazol-1-yl)propyl]phenoxyacetic acid,

17(i) 3-[3-(4-Diphenylmethylpyrazol-1-yl)-1-propenyl]phenoxyacetic acid,

17(j) 4-[2-(4-Diphenyimethylpyrazol-1-yl)ethyl]phenoxyacetic acid,

17(k) 4-[3-(4-Diphenylmethylpyrazol-1-yl)propyl]phenoxyacetic acid,

17(l) 4-[4-(4-Diphenylmethylpyrazol-1-yl)butyl]phenoxyacetic acid,

17(m) 3-[(4-Diphenylmethylpyrazol-1-yl)methyl]phenoxyacetic acid,

17(n) 2-[4-(4-Diphenylmethylpyrazol-1-yl)butyl]phenoxyacetic acid,

17(o) 3-[3-[4-[1-Phenyl-1-(3-pyridyl)methyl]pyrazol-1-yl]-1-propenyl]phenoxy acetic acid,

17(p) 2-Methoxy-5-[3(4-diphenylmethylpyrazol-1-yl)propyl]phenoxyaceticacid,

17(q)2-Nitro-5-[3-(4-diphenylmethylpyrazol-1-yl)-1-propenyl]phenoxyaceticacid,

17(r)4-Nitro-3-[3-(4-diphenylmethylpyrazol-1-yl)-1-propenyl]phenoxyaceticacid,

17(s)2-Methyl-3-[3-(4-diphenylmethylpyrazol-1-yl)-1-propenyl]phenoxyaceticacid,

17(t)2-Methyl-5-[3-(4-diphenylmethylpyrazol-1-yl)-1-propenyl]phenoxyaceticacid,

17(u)3-Methyl-5-[3-(4-diphenylmethylpyrazol-1-yl)-1-propenyl]phenoxyaceticacid,

17(v)4-Methyl-3-[3-(4-diphenylmethylpyrazol-1-yl)-1-propenyl]phenoxyaceticacid,

17(w)3-[2-[1-Phenyl-1-(3-pyridyl)methylideneaminooxy]ethyl]phenoxyaceticacid,

17(x)3-[3-[1-Phenyl-1-(3-pyridyl)methylideneaminooxy]propyl]phenoxyaceticacid,

17(y)2-[3-[1-Phenyl-1-(3-pyridyl)methylideneaminooxy]propyl]phenoxyaceticacid,

17(z)2-[4-[1-Phenyl-1-(3-pyridyl)methylideneaminooxy]butyl]phenoxyaceticacid,

17(aa) 2-[5-[1-Phenyl-1-(3-pyridyl)methylideneaminooxy]pentyl]phenoxyacetic acid,

17(bb)3-[3-[1-Phenyl-1-(3-pyridyl)methylideneaminooxy]-1-propenyl]phenoxyacetic acid,

17(cc) 3-[2-(4-Diphenylmethylpyrazol-1-yl)ethyloxy]phenoxyacetic acidand

17(dd) 3-[2-[1-Phenyl-1-(3-pyridyl)methylideneaminooxy]ethyloxy]phenoxyacetic acid.

EXAMPLE 18 Methyl3-[3-(5-diphenylmethylisoxazol-3-yl)propyl]phenoxyacetate ##STR145##

To a suspension of the compound prepared in reference example 16 (300mg), potassium bicarbonate (138 mg)in dimethylformamide (4.0 ml) wasadded dropwise and methyl bromoacetate (0.095 ml) was added withstirring at room temperature. The mixture was stirred for 5 h at 50° C.The mixture was poured into water and extracted with ethyl acetate. Theextract was washed with water and saturated aqueous solution of sodiumchloride, successively, dried over anhydrous magnesium sulfate andevaporated. The residue was purified by silica gel column chromatography(benzene:ethyl acetate=19:1) to give the title compound (350 mg) havingthe following physical data.

TLC: Rf 0.22 (ethyl acetate:n-hexane=1:3);

NMR: δ7.37-7.02 (11H, m), 6.85-6.67 (3H, m), 5.72 (1H, s), 5.51 (1H, s),4.62 (2H, s), 3.79 (3H, s), 2.72-2.57 (4H, m), 2.05-1.86 (2H, m).

EXAMPLE 19 3-[3-(5-diphenylmethylisoxazol-3-yl)propyl]phenoxyacetic acid##STR146##

To a solution of the compound prepared in example 18 (295 mg) intetrahydrofuran (2.0 ml) and methanol (1.0 ml) was added dropwise 1Naqueous solution of sodium hydroxide (1.0 ml) with stirring at roomtemperature. After being stirred for 30 min at room temperature, themixture was neutralized by addition of 1N hydrochloric acid and wasextracted with ethyl acetate. The extract was washed with water and asaturated aqueous solution of sodium chloride successively, dried overanhydrous magnesium sulfate, and evaporated. The residue was purified bysilica gel column chromatography (chloroform:methanol=49:1→9:1) to givethe title compound (208 mg) having the following physical data.

TLC: Rf 0.25 (chloroform:methanol=4:1);

IR [KBr tablet method] (cm⁻¹): ν3401, 3028, 2924, 1796, 1494, 1452,1425, 1340, 1248, 1160, 1078, 900, 791, 752, 699.

EXAMPLE 19(a)-19(b)

By the same procedure as in reference example 14→reference example16→example 18→example 19, using the compound prepared in referenceexample 23 and by the same procedure as in reference example 16 →example18→example 19, using the compound prepared in reference example 25,compounds having the following physical data shown in the table 6 weregiven.

                                      TABLE 6                                     __________________________________________________________________________    EX.                                                                           No.                                                                              Structure of the example compound                                                                          TLC (Rf)                                                                             NMR (δ)                          __________________________________________________________________________    19(a)                                                                             ##STR147##                  0.14 (chloroform: methanol= 9:1)                                                     7.4-6.5(1H, brs), 7.38-7.14(11H,                                              m), 6.82(1H, d), 6.77-6.72(2H, m),                                            .81(1H, s), 5.55(1H, s), 4.65(2H,                                             s), 2.71(2H, t), 2.65(2H, t),                                                 2.09-1.92(2H, m).                      19(b)                                                                             ##STR148##                  0.19 (chloroform: methanol= 17:3)                                                    7.35-7.12(11H, m), 6.84-6.69(4H,                                              m), 5.97(1H, brs), 5.66(1H, s),                                               4.64(2H, s), 2.85(2H, t), 2.64(2H,                                            t), 2.08-1.90(2H,                      __________________________________________________________________________                                           m).                                

The example compounds shown in table 6 are named as follows:

19(a) 3-[3-(3-Diphenylmethylisoxazol-5-yl)propyl]phenoxyacetic acid and

19(b) 3-[3-(3-Diphenylmethylisothiazol-5-yl)propyl]phenoxyacetic acid.

EXAMPLE 20 Methyl3-[3-(3-diphenylmethyl-1,2,4-oxadiazol-5-yl)propyl]phenoxy acetate##STR149##

A solution of the compound prepared in reference example 17 (193 mg) intoluene (8 ml) was refluxed overnight. The mixture was evaporated. Theresidue was purified by flash silica gel chromatography (n-hexane:ethylacetate=4:1) to give the title compound (108 mg) having the followingphysical data.

NMR: δ7.40-7.10 (11H, m), 6.90 (1H, d, J=7Hz), 6.75 (1H, s), 6.72 (1H,d, J=7Hz), 5.58(1H, s), 4.60 (2H, s), 3.79 (3H, s), 2.87 (2H, t, J=7Hz),2.67 (2H, t, J=7Hz), 2.11 (2H,m);

MS(m/z): 442 (M⁺), 250, 167.

EXAMPLE 213-[3-(3-diphenylmethyl-1,2,4-oxadiazol-5-yl)propyl]phenoxyacetic acid##STR150##

By the same procedure as in example 2, using the compound prepared inexample 20 (108 mg), the title compound (102 mg) having the followingphysical data was given.

TLC: Rf 0.16 (chloroform:methanol=9:1);

NMR: δ7.40-7.10 (11H, m), 6.90-6.70 (3H, m), 5.59 (1H, s), 4.62 (2H, s),2.87 (2H, t, J=7Hz), 2.68 (2H, t, J=7Hz), 2.12 (2H, m).

EXAMPLE 22 Methyl3-[3-(5-diphenylmethyl-1,2,4-oxadiazol-3-yl)propyl]phenoxy acetate##STR151##

A solution of the compound prepared in reference example 20 (61 mg) intoluene (8.0 ml) was refluxed overnight. The mixture was evaporated. Theresidue was purified by flash silica gel chromatography (n-hexane:ethylacetate=4:1) to give the title compound (31 mg) having the followingphysical data.

NMR: δ7.40-7.10 (11H, m), 6.82 (1H, d, J=7Hz), 6.78 (1H, s), 6.74 (1H,d, J=7Hz), 5.70 (1H, s), 4.60 (2H, s), 3.80 (3H, s), 2.76 (2H, t,J=7Hz), 2. J=7Hz), 2.08 (2H, m);

MS (m/z): 442 (M⁺), 251, 167.

EXAMPLE 233-[3-(5-diphenylmethyl-1,2,4-oxadiazol-3-yl)propyl]phenoxyacetic acid##STR152##

By the same procedure as in example 2, using the compound prepared inexample 22 (31 mg), the title compound (30 mg) having the followingphysical data was given.

TLC: Rf 0.18 (chloroform:methanol=9:1);

NMR: δ7.40-7.10 (11H, m), 6.84(1H, d, J=7Hz), 6.77(1H, s), 6.74 (1H, d,J=7Hz), 5.72 (1H, s), 4.63 (2H, s), 2.74 (2H, t, J=7Hz), 2.67 (2H, t,J=(2H, m).

Formulation example 1

The following components were admixed in a conventional method andpunched out to obtain 100 tablets each containing 5 mg of activeingredient.

    ______________________________________                                        3-(4-Diphenylmethyloxyiminobutyl)phenoxy                                                               500     mg                                           acetic acid                                                                   Carboxymethylcellulose calcium                                                                         200     mg                                           Magnesium stearate       100     mg                                           Microcrystalline cellulose                                                                             9.2     g                                            ______________________________________                                    

Formulation example 2

The following components were admixed in a conventional manner. Thesolution was sterilized in conventional manner, portions were placed 5ml into 10 ml ampoules and freeze-dried to obtain 100 ampoules eachcontaining 2 mg of the active ingredient.

    ______________________________________                                        3-(4-Diphenylmethyloxyiminobutyl)phenoxy                                                               200     mg                                           acetic acid                                                                   Citric acid, anhydrous   20      mg                                           Distilled water          500     ml                                           ______________________________________                                    

"While the invention has been described in detail and with reference tospecific examples thereof, it will be apparent to one skilled in the artthat various changes and modifications can be made therein withoutdeparting from the spirit and scope thereof."

What is claimed is:
 1. A Phenoxyacetic acid derivative of the formula(I): ##STR153## wherein A is ##STR154## T is i) single bond,ii) C1-6alkylene, iii) C2-6 alkenylene or iv) --O--(CH₂)_(s) --; D isi) --CO₂R¹⁰ or ii) --CONR¹¹ R¹² ; m is 1-3, wherein when m is 1, R⁹ is a C1-4alkyl substituted by one or two of phenyl or 4-7 membered monocyclichetero ring containing one nitrogen, and when m is 2 or 3, at least oneR⁹ is a C1-4 alkyl substituted by one or two of phenyl or 4-7 memberedmonocyclic hetero ring containing one nitrogen and another R⁹ isi)hydrogen, ii) phenyl, iii) C1-4 alkyl or iv) C1-4 alkyl substituted byone or two of phenyl or 4-7 membered monocyclic hereto ring containingone nitrogen; R¹⁰ is hydrogen or C1-12 alkyl; R¹¹ and R¹² each,independently, is hydrogen or C1-4 alkyl or R¹¹ and R¹², taken togetherwith nitrogen bond to R¹¹ and R¹² is the residue of an amino acid; R¹³is hydrogen, C1-4 alkyl, C1-4 alkoxy or nitro; s is 2-4;and the R⁹ ringsmay be substituted by one to three of C1-C4 alkyl, C1-C4 alkoxy,halogen, nitro or trihalomethyl; non-toxic salts thereof or non-toxicacid addition salts thereof.
 2. A compound according to claim 1, whereinD is carboxy.
 3. A compound according to claim 1, wherein D is C1-12alkoxycarbonyl.
 4. A compound according to claim 1, wherein D is CONR¹¹R¹² in which R¹¹ and R¹² are the same meaning as defined in claim
 1. 5.A compound according to claim 1, whichis3-[3-(4-Diphenylmethylpyrazol-1-yl)propyl]phenoxyacetic acid,3-[4-(4-Diphenylmethylpyrazol-1-yl)butyl]phenoxyacetic acid,2-[4-(4-Diphenylmethylpyrazol-1-yl)butyl]phenoxyacetic acid,2-[5-(4-Diphenylmethylpyrazol-1-yl)pentyl]phenoxyacetic acid,3-[2-(4-Diphenylmethylpyrazol-1-yl)ethyl]phenoxyacetic acid,2-[3-(4-Diphenylmethylpyrazol-1-yl)propyl]phenoxyacetic acid,3-[3-(4-Diphenylmethylpyrazol-1-yl)-1-propenyl]phenoxyacetic acid,4-[2-(4-Diphenylmethylpyrazol-1-yl)ethyl]phenoxyacetic acid,4-[3-(4-Diphenylmethylpyrazol-1-yl)propyl]phenoxyacetic acid,4-[4-(4-Diphenylmethylpyrazol-1-yl)butyl]phenoxyacetic acid,3-[(4-Diphenylmethylpyrazol-1-yl)methyl]phenoxyacetic acid,2-[4-(4-Diphenylmethylpyrazol-1-yl)butyl]phenoxyacetic acid,3-[3-[4-[1-Phenyl-1-(3-pyridyl)methyl]pyrazol-1-yl]-1-propenyl]phenoxyaceticacid, 2-Methoxy-5-[3(4-diphenylmethylpyrazol-1-yl)propyl]phenoxyaceticacid,2-Nitro-5-[3-(4-diphenylmethylpyrazol-1-yl)-1-propenyl]phenoxyaceticacid,4-Nitro-3-[3-(4-diphenylmethylpyrazol-1-yl)-1-propenyl]phenoxyaceticacid,2-Methyl-3-[3-(4-diphenylmethylpyrazol-1-yl)-1-propenyl]phenoxyaceticacid,2-Methyl-5-[3-(4-diphenylmethylpyrazol-1-yl)-1-propenyl]phenoxyaceticacid,3-Methyl-5-[3-(4-diphenylmethylpyrazol-1-yl)-1-propenyl]phenoxyaceticacid,4-Methyl-3-[3-(4-diphenylmethylpyrazol-1-yl)-1-propenyl]phenoxyaceticacid, 3-[2-(4-Diphenylmethylpyrazol-1-yl)ethyloxy]phenoxyacetic acid,3-[3-[4-Di(3-pyridyl)methylpyrazol-1-yl]propyl]phenoxyacetic acid,2-Methyl-3-[3-[4-[1-phenyl-1-(3-pyridyl)metyl]pyrazol-1-yl]propyl]phenoxyacetic acid,3-[2-[4-[1-Phenyl-1-(3-pyridyl)methyl]pyrazol-1-yl]ethyl]phenoxyaceticacid, or its methyl ester, or its octyl ester, or its acetamide, or itsamide with glycine.
 6. A pharmaceutical composition which comprises, asactive ingredient, an effective amount of a phenoxyacetic acidderivative of the formula (1) depicted in claim 1 or a non-toxic saltthereof, or a non-toxic acid addition salt thereof, with apharmaceutical carrier or coating.
 7. A method for the treatment ofthrombosis, arteriosclerosis, ischemic heart diseases, gastric ulcer orhypertension, which comprises administering an effective amount of aphenoxyacetic acid derivative of the formula (1) depicted in claim 1 ora non-toxic salt thereof, or a non-toxic acid addition salt thereof.